Clinical trial NCT02470234
Conditions: Attention-Deficit/Hyperactivity Disorder
Keywords: ADHD Children Pharmacokinetics
Sponsor: Rhodes Pharmaceuticals, L.P.
Start date: 2016-07-30; Completion date: 2017-08-07
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the pharmacokinetics of a single dose of Aptensio XR® (methylphenidate hydrochloride extended-release) capsules under fed conditions in male or female children 4 to under 6 years of age with ADHD.

Detailed description:
This will be a multi-center, open-label, single-dose, study to assess the pharmacokinetics of Aptensio XR® (methylphenidate hydrochloride extended-release) capsules in male and female children 4 to under 6 years of age with ADHD in fed condition.

Screening Procedures: After obtaining written informed consent from parents, subjects will undergo a complete medical and medication history, demographic data (including sex, age, race, ethnicity, body weight (kg), height (cm), Body Mass Index (BMI) (kg/m2), physical examination, vital signs evaluation (sitting blood pressure, pulse rate, respiration rate, temperature and pulse oximetry), resting 12-lead electrocardiogram (ECG), clinical laboratory tests and concomitant medication within 28 days prior to receiving study drug. On Day 1: subjects will receive a single oral dose of Aptensio XR®.

Arms: arm 1: Methylphenidate Hydrochloride Extended Release Capsules, 10 mg. Active drug, administered once arm 2: Methylphenidate Hydrochloride Extended Release Capsules, 15 mg. Active drug, administered once arm 3: Methylphenidate Hydrochloride Extended Release Capsules, 20 mg. Active drug, administered once
Interventions: intervention 1: Methylphenidate HCl ER Capsules, 10 mg intervention 2: Methylphenidate HCl ER Capsules, 15 mg intervention 3: Methylphenidate HCl ER Capsules, 20 mg
Intervention descriptions: intervention 1: Methylphenidate Hydrochloride Extended-Release Capsules, 10 mg administered once daily in the morning intervention 2: Methylphenidate Hydrochloride Extended-Release Capsules, 15 mg administered once daily in the morning intervention 3: Methylphenidate Hydrochloride Extended-Release Capsules, 20 mg administered once daily in the morning

Protocol documents:
Prot_SAP_000.pdf: 
Rhodes Pharmaceuticals, L.P. 
13 February 2018 
RP-BP-PK003, v2.0: Pharmacokinetics of Aptensio XR® in ADHD Children 4 to Under 6 Years of Age 
Page 1 of 36 
CONFIDENTIAL 
Rhodes Pharmaceuticals, L.P.  
IND 104,624 
CLINICAL PHARMACOLOGY STUDY PROTOCOL 
A  Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) 
Extended-Release capsules in Male or Female Pre-School Children 4 to Under 
6 years of age with ADHD in Fed Condition 
No. RP-BP-PK003, v2.0 
VERSION DATE 
13 February, 2018 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the study, without written authorization from Rhodes Pharmaceuticals or its 
affiliates. 


Rhodes Pharmaceuticals, L.P. 
13 February 2018 
RP-BP-PK003, v2.0: Pharmacokinetics of Aptensio XR® in ADHD Children 4 to Under 6 Years of Age 
Page 2 of 36 
A Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) 
Extended-Release Capsules in Male or Female Pre-School Children 4 to Under 6 
years of age with ADHD in Fed Condition 
Protocol Number: 
Sponsor: 
Sponsor Contact: 
Approved By: 
RP-BP-PK003, v2.0 
Rhodes Pharmaceuticals, L.P. 
498 Washington Street 
Coventry RI 02816 
Peter Haddock, PhD 
Associate Director, Clinical research 
Rhodes Pharmaceuticals, L.P. 
Phone: 401-262-9088 
Akwete Adjei, PhD 
Executive Director, Clinical research 
Rhodes Pharmaceuticals, L.P. 
Phone:401-262-9408 
Signature 
Robert J. Kupper, PhD 
Vice President & Chief Technical Officer 
Rhodes Pharmaceuticals, L.P. 
Phone:401-262-9193 
Date 
o 2./1 s-/ .:i. o I~ 
l 
I 
Date 


Rhodes Pharmaceuticals, L.P. 
13 February 2018 
RP-BP-PK003, v2.0: Pharmacokinetics of Aptensio XR® in ADHD Children 4 to Under 6 Years of Age 
Page 3 of 36 
INVESTIGATOR'S AGREEMENT 
I have read the protocol: 
RP-BP-PK003: A Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) 
Extended-Release Capsules in Male or Female Pre-School Children 4 to Under 6 years of age with 
ADHD in Fed Condition. 
I have fully discussed the objectives of this trial and the contents of this protocol with the Sponsor's 
representative. 
I understand that the information in this protocol is confidential and should not be disclosed, other 
than to those directly involved in the execution or the ethical review of the trial , without written 
authorization from Rhodes Pharmaceuticals. It is , however, permissible to provide information to a 
subject in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, subject to 
ethical and safety considerations and guidelines, and to conduct the trial in accordance with 
International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP) and 
with the applicable regulatory requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate the trial at any time for 
any reason; such a decision will be communicated to me in writing. Conversely, should I decide to 
withdraw from execution of the trial, I will communicate my intention immediately in writing to the 
Sponsor. 
Investigator Name and Address: 
Scott Kollins, Ph.D. 
Professor, Vice-Chair, Director 
Department of Psychiatry & Behavioral Sciences 
2608 Erwin Road, Suite 300 
Duke University, 
Durham, NC 27705 
(;RS-"-"~ A· 
Vl, \.\, ~'-.)V\ ~~-\- e' 
~~ 
~\~, 


Rhodes Pharmaceuticals, L.P. 
13 February 2018  
RP-BP-PK003, v2.0: Pharmacokinetics of Aptensio XR® in ADHD Children 4 to Under 6 Years of Age 
Page 4 of 36 
 
 
 
A Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) Extended-
Release Capsules in Male or Female Pre-School Children 4 to Under 6 Years of Age with 
ADHD in Fed Condition  
 
 
KEY STUDY PERSONNEL 
Principal Investigator: 
Scott Kollins, Ph.D. 
Professor, Vice-Chair, Director 
Department of Psychiatry & Behavioral 
Sciences 2608 Erwin Road, Suite 300 
Duke University, Durham, NC 27705 
Phone:  919-681-0014  
CRO Contacts: 
Shawnda Bertolini 
Sr. Project Manager 
MedSource 
16902 El Camino Real 
Houston, TX 77058 
Phone: 509-926-7248 
 
Laura Rohrbaugh 
Account Management 
Accenture Accelerated R&D Services 
1160 W. Swedesford Rd. Bldg. One 
Berwyn PA 19312 
Phone: 610-407-1828 
 
 
 


Rhodes Pharmaceuticals, L.P. 
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Page 5 of 36 
 
 
A Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) Extended-
Release, Capsules in Male or Female Pre-School Children 4 to Under 6 Years of Age with 
ADHD in Fed Condition 
 
STUDY FACILITIES 
Clinical Packaging: 
Business Development Manager 
Almac Clinical Services 
25 Fretz Road  
Souderton, PA 18964 
Phone: 215-660-8500 
Clinical Services: 
eResearchTechnology, Inc (ERT)  
1818 Market Street 
Suite 1000 
Philadelphia, PA 19103 
Phone: 215-282-5918 
 
Bioanalytical Laboratory: 
Worldwide Clinical Trials Early Phase Services 
Bioanalytical Sciences, Inc. 
8609 Cross Park Drive 
Austin, Texas 78754 
Phone: 512.834.7766 
Fax:  512-834-1165 
Pharmacokinetics: 
Worldwide Clinical Trials Early Phase Services/ 
Bioanalytical Sciences, Inc. 
8609 Cross Park Drive  
Austin, Texas 78754 
Phone: 512-834-7766 
Fax:  512-834-1165 
Statistics: 
Worldwide Clinical Trials Early Phase Services 
Bioanalytical Sciences, Inc. 
8609 Cross Park Drive Austin, Texas 78754 
Phone: 512-834-7766 
Fax:  512-834-1165 
 
Accenture Life Sciences 
1160 W. Swedesford Road 
Building One 
Berwyn PA 19312 
Phone: 610-407-1828 
 
 


Rhodes Pharmaceuticals, L.P. 
13 February 2018  
RP-BP-PK003, v2.0: Pharmacokinetics of Aptensio XR® in ADHD Children 4 to Under 6 Years of Age 
Page 6 of 36 
 
 
 
Institutional Review Board: 
Western Institutional Review Board 
1019 39th Avenue SE Suite 120 
Puyallup, WA 98374-2115 
Phone: 360-252-2500; 800-562-4789 
FAX: 360-252-2498
 
 
 


Rhodes Pharmaceuticals, L.P. 
13 February 2018  
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Table of Contents 
 
PROTOCOL SYNOPSIS ................................................................................................................................................. 11 
1 
INTRODUCTION ................................................................................................................................................. 14 
1.1 
Attention Deficit Hyperactivity Disorder Overview: ........................................................................ 14 
1.2 
Methylphenidate Overview: .............................................................................................................. 15 
1.3 
Pharmacokinetics of Methylphenidate: ............................................................................................. 15 
1.4 
Rationale of Dosing: ......................................................................................................................... 16 
2 
OBJECTIVE .......................................................................................................................................................... 17 
3 
STUDY DESIGN SUMMARY: ........................................................................................................................... 17 
3.1 
Open-Label, Long-Term, Extension Study ....................................................................................... 17 
4 
SUBJECT SELECTION ....................................................................................................................................... 19 
4.1 
Inclusion Criteria .............................................................................................................................. 19 
4.2 
Exclusion Criteria ............................................................................................................................. 19 
4.3 
Inclusion of subjects without prior non-pharmacological therapy .................................................... 20 
4.4 
Restrictions ....................................................................................................................................... 20 
4.5 
Screening ........................................................................................................................................... 20 
4.5.1 
Clinic - Day (-5): ....................................................................................................................... 21 
4.5.2 
Clinic - Day (-1): ....................................................................................................................... 21 
4.5.3 
Clinic – Day (1): ....................................................................................................................... 21 
4.5.4 
End of Study Visit: .................................................................................................................... 21 
4.6 
Laboratory Tests ........................................................................................................................... 21 
4.6.1 
Hematology ............................................................................................................................... 21 
4.6.2 
Serum Chemistry....................................................................................................................... 22 
4.6.3 
Serology .................................................................................................................................... 22 
4.6.4 
Urinalysis .................................................................................................................................. 22 
5 
STUDY PROCEDURES ....................................................................................................................................... 22 
5.1 
Subject Assignment........................................................................................................................... 22 
5.2 
Check-In Procedures ......................................................................................................................... 22 
5.3 
Confinement ...................................................................................................................................... 22 
5.4 
Meals/Beverages ............................................................................................................................... 22 
5.4.1 
Meals ......................................................................................................................................... 22 
5.4.2 
Beverages .................................................................................................................................. 22 
5.5 
Drug Administration ......................................................................................................................... 23 
5.5.1 
Administration of Study Medication ......................................................................................... 23 
5.5.2 
Blood Sampling, Processing and Shipment .............................................................................. 23 
5.6 
End-of-Study Procedures .................................................................................................................. 24 


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5.7 
Safety Monitoring and Procedures .................................................................................................... 24 
6 
ADVERSE EVENTS ............................................................................................................................................ 24 
6.1 
Definitions ......................................................................................................................................... 25 
6.1.1 
Adverse Event ........................................................................................................................... 25 
6.1.2 
Life-Threatening Adverse Event/Life-Threatening Suspected Adverse Reaction .................... 25 
6.1.3 
Serious Adverse Event/Serious Suspected Adverse Reaction .................................................. 25 
6.1.4 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction .................................... 25 
6.2 
Serious Adverse Event Reporting ..................................................................................................... 25 
6.3 
Relationship to Study Treatment ....................................................................................................... 26 
7 
GENERAL CONSIDERATIONS ......................................................................................................................... 27 
7.1 
Basic Principles ................................................................................................................................. 27 
7.2 
Protocol Approval ............................................................................................................................. 27 
7.3 
Institutional Review Board ............................................................................................................... 27 
7.4 
Informed Consent Form and Assent ................................................................................................. 27 
7.5 
Investigator’s Brochure ..................................................................................................................... 27 
7.6 
Protocol Modifications ...................................................................................................................... 27 
7.7 
Qualified Investigator Undertaking .................................................................................................. 28 
7.8 
Indications for Subject Withdrawal .................................................................................................. 28 
7.9 
Termination of the Study .................................................................................................................. 28 
7.10 
Treatment of Outliers ........................................................................................................................ 28 
7.11 
Documentation .................................................................................................................................. 28 
7.12 
Trial Monitoring ................................................................................................................................ 29 
7.13 
Reimbursement, Indemnity, and Insurance ....................................................................................... 29 
7.14 
Quality Control and Quality Assurance Audits ................................................................................ 29 
7.15 
Archiving .......................................................................................................................................... 29 
7.16 
Confidentiality of Data ...................................................................................................................... 29 
7.17 
Publication Policy ............................................................................................................................. 29 
7.18 
Investigator Responsibilities ............................................................................................................. 29 
8 
PHARMACOKINETIC ANALYSIS .................................................................................................................... 30 
8.1 
Analytical Methodology ................................................................................................................... 30 
8.2  
Pharmacokinetic Parameters ............................................................................................................. 30 
8.3 
Statistical Analysis ............................................................................................................................ 31 
9 
FACILITIES .......................................................................................................................................................... 31 
10 
DRUG SUPPLIES ................................................................................................................................................. 32 
11 
FINAL REPORT ................................................................................................................................................... 32 
12 
ADMINISTRATIVE ISSUES ............................................................................................................................... 32 
13 
REFERENCES ...................................................................................................................................................... 33 
14 
APPENDICES ....................................................................................................................................................... 36 


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13 February 2018  
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14.1. 
K-SADS-PL .................................................................................................................................. 36 
14.2 
ADHD Rating Scale (ADHD-RS-IV) Preschool Version................................................................. 36 
14.3 
Clinical Global Impressions-Severity (CGI-S) Scale ....................................................................... 36 
14.4 
Children’s Global Assessment Scale (CGAS) .................................................................................. 36 
 
 
 


Rhodes Pharmaceuticals, L.P. 
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Table of Tables: 
Table 1: Schedule of Events .............................................................................................................................. 18 
Table 2: Schedule of Vital Signs Measurements ............................................................................................... 24 
 
 
 


Rhodes Pharmaceuticals, L.P. 
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PROTOCOL SYNOPSIS 
 
Protocol #: 
RP-BP-PK003 Version 2.0 
Compound: 
Methylphenidate Hydrochloride 
Study Title: 
A Pharmacokinetic Study of Aptensio XR® (Methylphenidate Hydrochloride) Extended-Release 
Capsules in Male or Female Pre-School Children 4 to Under 6 Years of Age with ADHD in Fed 
Condition 
Study 
Objectives: 
To assess the pharmacokinetics of a single dose of Aptensio XR® (Methylphenidate 
Hydrochloride) Extended-Release capsules under fed conditions in male or female children 4 to 
under 6 years of age with ADHD. 
Approximate 
Number of 
Subjects 
Screened: 
60 
Number of 
Subjects to 
Complete 
Ten (10) 
Study Design, 
Duration of 
Treatment: 
This will be a multi-center, open-label, single-dose, study to assess the pharmacokinetics of 
Aptensio XR® (Methylphenidate Hydrochloride) Extended-Release capsules in male and 
female children 4 to under 6 years of age with ADHD in fed condition. 
Dosage 
10, 15, 20, 30, and 40 mg capsules 
Study 
Duration: 
Approximately: 1 year, including screening period and treatment period 
Inclusion 
Criteria: 
1. Patient is a male or female between the ages of 4 and under 6 years old. 
2. Patient has a history consistent with ADHD, meets the DSM-IV criteria for ADHD, 
inattentive, hyperactivity or combined. 
3. Patient must meet criteria for ADHD diagnosis on KSADS-PL and clinical interview by 
experienced clinician; symptoms must have been present for at least 6 months. 
4. Subject has had prior behavioral treatment or subject’s symptoms are severe enough to 
warrant treatment without prior behavioral treatment, and patient is on a stable dose of 
either immediate-release or extended-release methylphenidate. 
5. Subject must have age- and sex-adjusted ratings of  ≥ 90th percentile Total Score on the 
ADHD-RS-IV Preschool Version, a Clinical Global Impressions -Severity Score of ≥4 and a 
Child Global Assessment Scale rating of <65 after methylphenidate washout and prior to 
obtaining pharmacokinetic samples.  Ratings may be completed via telephone on day-1. 
6. Parents or guardians of patients must have the ability to read and understand the 
language in which the Informed Consent is written and are mentally and physically 
competent to provide written informed consents for their child. 
7. Patient and/or parent are/is able to understand English in order to provide assent and is 
otherwise able to comply with the study protocol. 


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Exclusion 
Criteria: 
1. Patient has allergy to methylphenidate or amphetamines, or history of serious adverse 
reaction to methylphenidate. 
2. Patient has a history of tension, agitation, glaucoma, thyrotoxicosis, tachyarrythmias or 
severe angina pectoris or patient with serious or unstable medical illness such as asthma, 
diabetes, or seizures. 
3. A history of motor or vocal tics or Tourette’s syndrome 
4. Patient is receiving MAO inhibitors, anticonvulsants (phenobarbital, phenytoin, 
primidone), coumarin anticoagulants, presser agents guanethidine, tricyclic 
antidepressants (imipramine, desipramine, selective serotonin inhibitors (SSRIs), or 
herbal remedies (e.g., melatonin). 
5. Patient has serious hypertension. 
6. Patient has a history of disorders of the sensory organs, particularly deafness, severe or 
profound retardation. 
7. Patient has any other unstable psychiatric condition requiring treatment. 
8. Patient is at risk for substance abuse. 
9. Evidence of current physical, sexual, or emotional abuse 
10. Living with anyone who currently abuses stimulants or cocaine  
11. History of bipolar disorder in both biological parents 
Study 
Procedures: 
Screening Procedures: After obtaining written informed consent from parents, subjects will 
undergo a complete medical and medication history, demographic data (including sex, age, 
race, ethnicity, body weight (kg), height (cm), BMI (kg/m2), physical examination, vital signs 
evaluation (sitting blood pressure, pulse rate, respiration rate, temperature and pulse 
oximetry), resting 12-lead electrocardiogram (ECG), clinical laboratory tests and concomitant 
medication within 28 days prior to receiving study drug.  
On Day 1: subjects will receive a single oral dose of Aptensio XR® (Methylphenidate 
Hydrochloride) Extended-Release. 
Confinement 
and Visits; 
Subject will be confined in a play school setting for at least 12 hours after dosing after first 
blood draw. Subjects will return for all subsequent blood draws. 
Washout 
Medication discontinued 5 days prior to dosing (i.e., no dose on Day -5) 
Sample 
Collection, 
Processing, and 
Storage 
A local, topical anesthetic (2.5% lidocaine and 2.5% prilocaine cream) will be applied at the 
catheter insertion site. Serial Blood samples will be obtained via a catheter placed in the 
antecubital vein in subject’s forearm. Subjects will be distracted which includes listening to 
songs during catheter insertion and PK sampling. Serial blood samples for determination of 
methylphenidate plasma concentration and PK analysis will be obtained on Day 1 at time 0 
(within 15-30 minutes pre-dose) and 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose in 
K2EDTA Vacutainer tubes. The blood samples will be processed immediately by centrifugation, 
and the plasma samples will be stored at approximately -20°C before frozen shipment on dry ice 
and shipped to Bioanalytical CRO (Worldwide Clinical Trials). Samples will remain frozen 
until assayed. 
Bioanalytical 
Analysis: 
Plasma samples will be analyzed by high-performance liquid chromatography/mass 
spectrometry (LC/MS) to determine the concentrations of methylphenidate. 
Subject Safety 
Vital signs, ECG, medical history, physical examination, and clinical laboratory tests within 28 
days prior to receiving drug. 
Study Exit 
Procedures 
Vital signs, ECG, brief physical examination, laboratory tests, concomitant medications, and 
adverse events (AEs) 


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Study Endpoints: The primary PK endpoints include  
• 
Maximum plasma methylphenidate concentration (Cmax) and dose normalized 
(Cmax/Dose) 
• 
Area under the plasma concentration versus time curve calculated to the last measurable 
observation (AUC0-t) and dose normalized (AUC0-t/Dose) 
• 
Area under the plasma concentration versus time curve extrapolated to infinity (AUC0-inf) 
and dose normalized (AUC0-inf/Dose) 
• 
Apparent clearance (CL/F, where F is fraction of dose determined by bioavailability) and 
weight normalized (CL/F/Kg) using screening weight 
• 
Apparent volume of distribution (Vd/F) and weight normalized Vd/F/Kg using screening 
weight 
• 
Dose and weight normalized dose (mg/kg) 
The secondary PK endpoints include 
• 
Time to Cmax (tmax); 
• 
Elimination half-life (t½) 
• 
Terminal elimination rate constant (Kel) 
• 
AUC0-4 
• 
AUC4-8 
• 
AUC8-12 
Statistical 
Analyses: 
Statistics will be conducted on PK parameters. The arithmetic mean (SD) for Cmax, AUC, half-
life, Kel and median Tmax will be calculated. The SAP is attached. 
Safety Plan: 
During treatment, investigators will actively solicit reports of adverse events that will be 
recorded and assessed for severity and relationship to study medication. Safety assessments 
will include physical examinations, vital signs and blood counts at screening and after 
management with study medication. Vital signs will be assessed pre-dose, and then at 
specified hours. 
Adverse 
Events 
The safety and tolerability of methylphenidate, as assessed by incidence of treatment emergent 
adverse events (AEs) will be monitored by nursing and medical staff throughout the study and 
will be recorded 
Concomitant 
Medication: 
No other CNS stimulant other than the test medication specifically indicated for the treatment 
of ADHD will be administered during the course of study. Any concomitant medication will 
be recorded 
Scientific and 
Ethical 
Guidelines 
This study will be conducted according to the protocol, current ICH and GCP guidelines, the 
“Declaration of Helsinki” (2008) and all applicable Federal and local government regulations 
and Institutional research policies and procedures. 
IRB Approval 
The study will be conducted with the approval of a duly constituted institutional review board 
(IRB) or ethics committee (EC) in accordance with the requirement of 21 CFR 56 
- Institutional Review Boards. 


Rhodes Pharmaceuticals, L.P. 
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1 
INTRODUCTION 
1.1 
Attention Deficit Hyperactivity Disorder Overview: 
Disturbances in attention regulation and activity modulation are perhaps the most common 
psychiatric disorders in children1 with reported rates ranging from 4%2 to 9%.3 It is four to five times 
more frequent in boys than girls.4 Attention Deficit Disorder (ADD) is characterized by inattention 
and impulsivity and may be present with hyperactivity (ADHD).1 
 
Children affected by ADHD commonly exhibit disruptive behavior in the classroom, underachieve 
academically, and tend to have conflictual relations with family members and peers.5 They 
experience an inability to sit still and pay attention in class and the negative consequences of such 
behaviour.6 Other characteristics may include aggressiveness, stealing, lying, truancy, setting fires, 
running away, explosiveness, cognitive and learning problems as well as poor social skills.4 Their 
academic and social difficulties have far-reaching and long term consequences.6 For many 
individuals, the impact of ADHD continues into adulthood.6 
 
The DSM-IV defines ADHD as a persistent pattern of inattention/hyperactivity-impulsivity that is 
more frequent and severe than is typically observed in individuals at a comparable level of 
development.7 the exact cause of ADHD is not clear, although brain-imaging studies have suggested 
that the pre-frontal cortex and the basal ganglia are involved. These areas are responsible for 
“editing” one’s behavior and resisting distractions.8, 9 Other factors include premature birth, maternal 
alcohol and tobacco use, exposure to lead in early childhood and brain injuries – especially those that 
involve the prefrontal cortex.8 Although minimal degrees of head trauma may result in ADD, for the 
most part, children with ADD do not show evidence of a history of insult.1 
 
The mode of therapeutic action of stimulants in ADHD is not completely understood. There is some 
evidence suggesting that the mechanism whereby methylphenidate produces its mental and 
behavioral effects is related to a dose-dependent blockade of the dopamine transporter and an increase 
in extracellular dopamine.10, 11, 12, 13, 14 Methylphenidate is a racemic mixture comprised of the d- and 
l-isomers. Only the d-isomer possesses motor stimulant effects.15 
 
Methylphenidate should be administered starting at the lowest possible dose. The recommended 
starting dose of methylphenidate immediate-release tablet in children and adolescents is 5-10 mg 
three times daily with weekly increments of 5 to 10 mg in the daily dosage. In adults, the daily dosage 
with the immediate-release tablet ranges between 10 and 60 mg, with an average of 20 to 30 mg. The 
recommended starting dose of methylphenidate extended-release capsule in adults is 10 to 20 mg 
once daily and dosage may be adjusted to a maximum of 80 mg taken once daily. Adverse events 
associated with the use of immediate-release methylphenidate are listed in the product monograph.16 
 
Methylphenidate formulations are rapidly absorbed and reach peak (Cmax) values within 1 to 3 hours 
following oral ingestion (Ritalin® Label, Concerta® Label, Metadate® Label and Quillivant™ 
Label).16, 17, 18, 19 Extended-Release (ER) methylphenidate formulations usually produce two Cmax 
values in children and healthy adults, first peak at 1 to 3 hours and second peak occurs 3 to 4 hours 
later (Concerta®, Quillivant™).17, 19   ER formulations minimize variability between peak and trough 
levels that usually occurs with multiple dosing of Immediate-Release (IR) formulations. 
Bioavailability was similar upon administration of equivalent doses of IR or ER formulations. 


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Absorption of methylphenidate is essentially complete and rapid, as shown by urinary excretion and 
minimal fecal elimination.  After oral administration of 14C-methylphenidate dose, 50 to 90% of the 
radioactivity was excreted in urine by 8 to 48 hrs, respectively and fecal elimination accounted for 
1.5% and 3.3% of radioactive dose, respectively.20 
 
Methylphenidate is metabolized primarily by de-esterification to the inactive metabolite ritalinic 
acid.21, 22, 23   This facile process limits the absolute bioavailability to 11 to 53%.24   The circulating 
concentrations of ritalinic acid greatly exceed that of the parent drug 25, 26 and urinary elimination of 
ritalinic acid accounts for 60 to 80% of the dose.20, 21 
 
Methylphenidate is excreted almost entirely in the urine, mainly as alpha-phenyl-piperidine acetic 
acid (PPAA). Methylphenidate and its metabolites exhibit low plasma protein binding (~15%).27, 28 
 
There are no clinically significant food effects on methylphenidate bioavailability and this can be 
administered without regard to food intake (Ritalin® Label, Concerta® Label, Quillivant™ Label).16, 
17, 19. 
1.2 
Methylphenidate Overview: 
Methylphenidate {dl-threo-methyl-2-phenyl-2-(2-piperidyl) acetate} is the psychostimulant used 
most frequently in the treatment of hyperactivity and attention deficit disorder. It appears to have a 
higher incidence of positive effects and a lower incidence of adverse effects than other 
psychostimulants.29 
 
The psychopharmacologic features of methylphenidate (effects on motor performance and activity, 
effects on attention and impulsivity, and effects on cognition) have been reviewed by Shaywitz et al. 
(1984).1  Because the responses vary considerably at doses from 0.3 to 1.0 mg/kg, titration is required 
in each case.30 The smallest effective dose should be maintained. Many children show marked 
improvement with a single daily dose as low as 0.3 mg/kg; the need for a midday or midafternoon 
dose is easily determined and the effects are easily monitored.31 
 
The efficacy of methylphenidate in improving attention and behavioral symptoms has been supported 
by many studies. Short-term improvements in school-work production, accuracy and learning and the 
suggestion that treated children had been helped to take responsibility for the correction of their 
behavior were noted in a study by Douglas et al. (1985).32 
 
1.3 
Pharmacokinetics of Methylphenidate: 
Stimulant drugs have been used for the management of hyperactive children. However when first 
used very little was known about the pharmacology and metabolism of these agents, or about the 
relationship of blood levels to the clinical response.33 Peak blood levels following the administration 
of methylphenidate occur at 1 to 3 hours.20, 34 The half-life of the drug ranges from 2 to 4 hours in 
adults and children.20, 28, 35  Hungund et al. (1979) reported on the pharmacokinetics of 
methylphenidate in four hyperkinetic children.28 The mean half-life was 2.5 hours. Although there 
was little variability in this parameter, body clearance varied by a factor of three. This suggested that 
plasma methylphenidate levels are subject to a considerable degree of inter-patient variability. 
 


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The primary route of metabolism for methylphenidate is desterification to ritalinic acid, which 
accounts for 75% to 91% of total urinary methylphenidate. Other metabolic products arise from p-
hydroxylation or oxidation to the lactam. Gualtieri et al. (1982) reported on a series of bioavailability 
studies using a GC-mass spectrometric analysis to measure methylphenidate blood levels in 
hyperkinetic children (age 6-13 years), normal adults and hyperactive adults.36  The serial sampling 
study revealed adults had a pharmacokinetic profile similar to that in hyperkinetic children. The 
concentration time profile showed peak levels at 60 to 120 minutes. The peak concentrations had a 
four-fold range. Elimination half-lives showed a mean of 3.4 hours in adults and one adolescent, and 
ranged from 2.52 hours to 3.36 hours in children. In another series of studies, one hour serum levels 
were also measured in 16 hyperactive children, 28 hyperactive children and 22 healthy adult 
volunteers who were participating in placebo- controlled double-blind crossover studies of 
methylphenidate. There was the same wide range of serum levels noted in adults and children, and 
mean serum levels were virtually identical in adults and children. 
 
1.4 
Rationale of Dosing: 
Immediate-release methylphenidate preparations, because of their short half-life, require frequent 
administration at short intervals to ensure adequate treatment throughout a child’s school day. Their 
rapid onset and offset means that a medicated child with attention deficit disorder will be maximally 
affected only for relatively brief periods during the day. Due to its short half-life, methylphenidate is 
usually given twice per day, usually once after breakfast and once during the school day, an event that 
some children and some school personnel apparently avoid, resulting in poor compliance with 
prescribed regimens.37, 38  Compliance is a major problem for children who require a mid-day or mid-
afternoon dose as many schools prohibit children from taking medications during the school day and 
others often insist that all medications be given by a nurse.  
 
Poor compliance in taking medication may explain, in part, the variable and conflicting results 
reported in many studies of the effect of medication on improving the behavior of hyperactive 
children. These limitations of immediate-release methylphenidate led to interest in products with 
longer effective periods of action. Therefore, a methylphenidate sustained-release formulation was 
developed. This formulation was chosen for further development because it exhibited an initial rapid 
rise in plasma concentration in healthy adults (range 18-45 years) similar to Ritalin® with a Cmax 
relative to the first dose of Ritalin® IR, a relative Total AUC0-inf also similar to Ritalin® (study RP-
BP-PK001) and its plasma concentration time profile was more prolonged than that of Ritalin® IR. 
The elimination half-life of immediate-release methylphenidate in study (RP-BP-PK001) was 3.4 
hour fasting and 3.15 hours in the fed state, which is consistent with the findings of Gualtieri et al in 
adults and children.38, 39 Based upon the 90% CIs, maximum plasma methylphenidate concentrations 
(Cmax) and exposure (AUCs) were comparable following Aptensio XR® 80 mg capsule or Aptensio 
XR® 80 mg sprinkle once daily compared to comparator 3 × 25 mg Ritalin®.40  We hypothesize that 
the pharmacokinetics of this new formulation of extended-release methylphenidate will be suitable 
for once-daily dosing in young children. As requested by FDA, a pharmacokinetic study of Aptensio 
XR® is required in children aged 4 to under 6 year with ADHD. The maximum daily dose in this 
pharmacokinetic study will not exceed 40 mg/day in children. 
 
The clinical efficacy of Aptensio XR® was established in two, controlled trials in young children and 
adolescents. The primary efficacy endpoint of study (RP-BP-EF001) was met. The primary measure 
of efficacy was the comparison between the average of SKAMP Total Scores for the Aptensio XR® 


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and placebo arms across treatment assessment days during the Double-Blind phase for the Evaluable 
population. LS mean post-dose SKAMP Total score was significantly better for Aptensio XR® than 
for placebo (1.32 vs 2.18, p = 0.0001) with subjects receiving Aptensio XR® having significantly 
greater improvement in classroom behavior, written work, and general behavior compared with 
placebo. Once-daily Aptensio XR® was significantly better than placebo in treating children with 
ADHD in a double-blind manner in laboratory school setting.40 
Results from a parallel, double-blind, placebo-controlled study (RP-BP-EF002) demonstrated the 
efficacy of Aptensio XR® relative to placebo in the treatment of ADHD in children and adolescents 
ages 6 to 18 years (n=221).40 The primary efficacy endpoint of this study was met. The primary 
efficacy analysis was to analyze the decrease from baseline (Visit 2) to the end of Week 1 (Visit 3) in 
the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total score, comparing 
the 5 treatment groups (placebo, 10, 15, 20, and 40 mg/day Aptensio XR®). The overall test for 
whether all treatments had the same mean decrease was the primary result. There was a statistically 
significant difference among treatments (ANCOVA, treatment p = 0.0046), which indicates that there 
were differences among study treatments for how much the total score decreased during the Double-
Blind phase. 
 
In both studies, no major adverse events were observed other than known for other methylphenidate. 
 
2 
OBJECTIVE 
To assess the pharmacokinetics of a single dose of Aptensio XR® (Methylphenidate Hydrochloride) 
Extended-Release Capsules (MPH-MLR or Biphentin®) under fed conditions in male or female 
children 4 to under 6 years of age with ADHD. 
 
3 
STUDY DESIGN SUMMARY: 
This is a single-dose, open-label, one-period study in which approximately 60 children with ADHD 
subjects will be screened in order for ten (10) subjects to complete the study. Subjects will be 
assigned numbers in an ascending order, based on successful completion of the screening process. 
Patients who withdraw from the study will not be replaced. 
During the study period, 1.0 mL blood samples will be obtained prior to dose administration and at 
selected times through 24 hours after dose administration. A total of 11 pharmacokinetic blood 
samples will be collected from each subject. Plasma pharmacokinetic samples will be analyzed for 
methylphenidate using a validated analytical method. Appropriate pharmacokinetic parameters will 
be calculated for each formulation using non-compartmental methods. 
Eligible patients will receive a total daily dose equivalent to their current total methylphenidate daily 
dose as a sprinkle over apple sauce or yogurt.  
Table 1 summarizes events proposed for the study. 
3.1 
Open-Label, Long-Term, Extension Study 
Subjects may be eligible for participation in a 12-month open-label extension study of MPH-MLR if 
they complete the End of Study visit and do not have adverse events that suggest poor tolerability to 
MPH-MLR.  Subjects who enroll in the open-label extension may do so at the End of Study Visit. 


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Table 1: Schedule of Events 
Evaluations 
Screening 
Visit (Days 
-28 to -1) 
Day (-5) 
Day (-1) 
Day 1 
End of Study 
Hours after dosing 
 
 
 
 
0 
0.5 
1 
2 
3 
4 
6 
8 
10 
12 
241 
Informed Consent & Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical / Medication History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
K-SADS-PL Structured Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADHD-RS-IV Preschool version 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Child Global Assessment (CGAS) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Global Impressions-Severity (CGI-S) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discontinue current methylphenidate dosing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen for methylphenidate 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
Admission 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Verify Inclusion/Exclusion Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Resting 12-Lead ECG 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Clinical Laboratory/urine/ Serology Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Chemistry and Hematology
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Holter Monitor Application 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Holter Monitor Removal 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study Drug Dosing 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood for PK Analysis 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                           
1 End of Study Visit 
2 A complete physical examination will be performed at Screening and a limited physical examination will be performed prior to discharge from the study. 
3 Screening vital signs include sitting blood pressure, pulse rate, weight, height, temperature, respiration rate and pulse oximetry. Vital signs will be obtained within 60 minutes prior to 
dosing and prior to discharge from the study.  For full schedule of vital signs measurements see Table 2 


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4 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
All subjects must satisfy the following criteria to be considered for study participation: 
 Patient is a male or female between the ages of 4 and under 6 years old. 
 Patient has a history consistent with ADHD, meets the DSM-IV criteria for ADHD, 
inattentive, hyperactivity or combined.  
 Patient must meet criteria for ADHD diagnosis on K-SADS-PL and clinical interview by 
experienced clinician; symptoms must have been present for at least 6 months. 
 Subject has had prior behavioral treatment or patient’s symptoms are severe enough to 
warrant treatment without prior behavioral treatment, and patient is on a stable dose of either 
immediate-release or extended-release methylphenidate. 
 Subject must have age- and sex-adjusted ratings of ≥ 90th percentile Total Score on the 
ADHD-RS-IV Preschool Version, a Clinical Global Impressions-Severity Score of ≥4 and a 
Child Global Assessment Scale rating of <65 after methylphenidate washout and prior to 
obtaining pharmacokinetic samples.  Ratings may be completed via telephone on day-1. 
 Parents or guardians of patients must have the ability to read and understand the language in 
which the Informed Consent is written and are mentally and physically competent to provide 
written informed consents for their child. 
 Patient and/or parent are/is able to understand English in order to provide assent and is 
otherwise able to comply with the study protocol. 
4.2 
Exclusion Criteria 
Subjects will be excluded for any of the following: 
 Patient has allergy to methylphenidate or amphetamines, or history of serious adverse 
reaction to methylphenidate. 
 Patient has a history of tension, agitation, glaucoma, thyrotoxicosis, tachy-arrythmias or severe 
angina pectoris or patient with serious or unstable medical illness such as asthma, diabetes or 
seizures. 
 A history of motor or vocal tics or Tourette’s syndrome. 
 Patient is receiving MAO inhibitors, anticonvulsants (phenobarbital, phenytoin, primidone), 
coumarin anticoagulants, presser agents guanethidine, tricyclic antidepressants (imipramine, 
desipramine, selective serotonin inhibitors (SSRIs) or herbal remedies (e.g., melatonin). 
 Patient has serious hypertension. 
 Patient has a history of disorders of the sensory organs, particularly deafness, severe or 
profound retardation. 
 Patient has any other unstable psychiatric condition requiring treatment. 
 Patient is at risk for substance abuse. 


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 Evidence of current physical, sexual or emotional abuse 
 Living with anyone who currently abuses stimulants or cocaine 
 History of bipolar disorder in both biological parents. 
4.3 
Inclusion of subjects without prior non-pharmacological therapy 
Broad guidelines for consideration of inclusion of subjects without prior non-pharmacological 
therapy will include the following: 
 ADHD-RS Preschool Version score >50 
 CGI-S score >5 
 CGAS score <40 
Additional consideration will be given to (i) parent-reported behavioral severity, (ii) specific concerns 
regarding safety of the child in his/her environment and (iii) the investigator’s judgment regarding 
likelihood of success of non-pharmacologic therapy. 
Investigators will document the specific rationale for assessing severity and impairment in cases 
where children are to be enrolled without a history of non-pharmacological treatment. These cases 
will be reviewed by the medical monitor and/or the coordinating PI(s). 
4.4 
Restrictions 
Parent should not give any over the counter (OTC) medication to his/her child within 7 days prior to 
the first dose of study medication until the end-of-study visit without evaluation and approval by the 
study investigator. 
Parent must not give any other medication prior to the first dose of study medication until the end-of-
study visit other than prescribed to control ADHD without evaluation and approval by the study 
investigator. 
Parent must not give beverages and foods containing grapefruit, poppy seeds or caffeine/xanthine 
from 48 hours prior to the first dose of study medication until the end- of-study visit. Parents should 
avoid giving above products to his/her children; however, allowance for an isolated single incidental 
consumption may be evaluated and approved by the study investigator based on the potential for 
interaction with the study drug. 
4.5 
Screening 
The principal investigator and co-investigators will identify patients who meet the selection criteria.   
After parents give informed consent, screening may begin immediately or an appointment will be 
made for a screening visit. Each potential study patient will have the following assessments by the 
Investigator or designee within 28 days prior to study start: medical history and demographic data, 
including sex, age, race, ethnicity, body weight (kg), height (cm) and BMI (kg/m2).  The K-SADS-
PL, a semi-structured interview, will be administered by qualified and trained clinicians to confirm 
ADHD diagnosis and determine whether psychiatric comorbidities are present.   Each potential 
participant will receive a physical examination, ECG, lab sampling for hematology, serum chemistry 
and serological testing, and a urinalysis. A urine drug screen to confirm methylphenidate dosing will 
be performed. The ECG will be performed after subject has been in supine position for a minimum of 
5 minutes. Only medically healthy subjects with clinically acceptable laboratory profiles and ECGs 
will be enrolled in the study. The informed consent documents will be discussed with each parent, 


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and each individual parent will sign an informed consent document for the study prior to any study-
specific procedures being performed. The patient’s current total daily dose of immediate- release or 
extended-release methylphenidate will be recorded.  
4.5.1 Clinic - Day (-5): 
Patients who meet the entry criteria will discontinue their current methylphenidate medication to 
enable washout for a minimum of 5 days prior to dosing. 
4.5.2 Clinic - Day (-1): 
The parent will provide any updates to the child’s medical history, pre-existing conditions, 
concomitant medication information, and past or present difficulty with inattention, hyperactivity, 
impulsivity, defiance, conduct problems and developmental disabilities.  ADHD severity and 
functioning will be quantified prior to dosing using the (i) ADHD-RS-IV Preschool version, (ii) Child 
Global Assessment (CGAS) and (iii) Clinical Global Impressions-Severity (CGI-S) scales. 
4.5.3 Clinic – Day (1): 
On the day of dosing:  Vital signs will be measured as described in Table 2. An indwelling catheter 
will be inserted prior to the morning dose and a pre-dose plasma sample will be obtained. Patients 
will receive a total dose as single Aptensio XR® capsule. A standardized breakfast consisting of 
cereal with milk, juice and toast will be provided before dosing. Patients will be assigned to various 
regimens based on previously targeted methylphenidate dose. After receiving the morning dose, 
patients will remain in the clinic for 12 hours during which time plasma samples will be collected at 
0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose. 
 
During the day, patients will be provided with meals or snacks consisting of pizza, milk, juice or 
water or other age appropriate food. After the 12 hour sample, the catheter will be removed and the 
patients will be discharged. Patients will subsequently return to the clinic the following morning.  
 
Parents will be instructed not to give any CNS stimulant, including supplemental methylphenidate, 
other to what is prescribed by the principal investigator. 
4.5.4 End of Study Visit:   
The patient will return to the clinic the next morning for a 24 hour blood draw.  At this time, the 
patients will resume their usual treatment and will receive a single daily dose of CR or IR 
methylphenidate as per previous prescription.  The patient will complete end of study procedures as 
described in Section 5.6. 
4.6 
Laboratory Tests 
A Clinical Laboratory Improvement Amendments (CLIA) certified laboratory will perform the 
following clinical laboratory tests for this study: 
4.6.1 Hematology 
The following will be evaluated: hemoglobin, hematocrit, total and differential leukocyte count, red 
blood cell count (RBC), and platelet count. 


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4.6.2 Serum Chemistry 
The following will be evaluated: albumin, blood urea nitrogen (BUN), creatinine, total bilirubin, 
alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), sodium 
(Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase (LDH), calcium (Ca), uric acid, and 
glucose. 
4.6.3 Serology 
Blood will be tested for hepatitis B surface antigen, hepatitis C antibody, and human 
immunodeficiency virus (HIV). 
4.6.4 Urinalysis 
The following will be evaluated by an automated or manual urine “dipstick” method: pH, specific 
gravity, protein, glucose, ketones, bilirubin, blood, nitrite, leukocyte esterase, and urobilinogen. If 
protein, occult blood, nitrite, or leukocyte esterase values are out of range, a microscopic examination 
will be performed. 
5 
STUDY PROCEDURES 
5.1 
Subject Assignment 
Approximately sixty (60) subjects will be screened in this study. Ten (10) subjects will be selected for 
dosing. Each selected subject will receive an assigned treatment dose to equal the patient’s current 
total daily dose of immediate-release or extended-release methylphenidate. 
The maximum duration of the study from screening to study completion will be approximately 1 
year. This is an open-label study without treatment blinding. 
5.2 
Check-In Procedures 
Parents of patients will be asked to affirm that the exclusion criteria and restrictions have not been 
violated since the screening. Parent’s response will be documented. 
5.3 
Confinement 
Patient will be admitted to the research center at an appropriate time in the morning prior to study 
drug administration. Patients will be given breakfast. Subjects will remain in the research center until 
completion of the 12-hour procedures for each study period and return for outpatient visits at 
approximately 24 hours after dose. 
5.4 
Meals/Beverages 
5.4.1 Meals 
Patients will be given breakfast. A standardized breakfast consisting of cereal with milk, juice and 
toast will be provided before dosing. During the day, patients will be provided with meals or snacks 
consisting of pizza, milk, juice or water or other age appropriate food. 
5.4.2 Beverages 
Water will be allowed ad lib and will be encouraged to drink water. 


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5.5 
Drug Administration 
5.5.1 Administration of Study Medication 
Drug will be administered as a sprinkle over apple sauce or yogurt. 
5.5.2 Blood Sampling, Processing and Shipment 
A total of 11 mL (11 1 mL samples) will be collected for pharmacokinetic analysis. In addition, 
approximately 5 mL of blood will be collected for screening and the end-of-study clinical laboratory 
evaluations. The total volume of blood collected will not exceed 21 mL. 
A local, topical anesthetic (2.5% lidocaine and 2.5% prilocaine cream) will be applied at the catheter 
insertion site.  Serial Blood samples will be obtained via a catheter placed in the antecubital vein in 
subject’s forearm.  Subjects will be distracted which includes listening to songs during catheter 
insertion and PK sampling.  Serial blood samples for determination of methylphenidate plasma 
concentration and PK analysis will be obtained on Day 1 at time 0 (within 15-30 minutes pre-dose) 
and 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose in K2-EDTA Vacutainer tubes. Samples will 
immediately be placed in an ice bath where they will remain throughout processing.   
Blood samples collected up to and including 24 hours post-dose within ± 2 minutes of scheduled time 
will not be considered deviations, however, exact time will be recorded. Blood samples will be 
centrifuged at approximately 3000 rpm for 10 minutes at 4 degrees Centigrade. The resulting plasma 
samples will be harvested and transferred into two appropriately labeled polypropylene screw-cap 
tubes. Use tubes supplied by Simport, Part # T310-1A, 12.5 x 42 mm, 1.2 mL tubes. Pharmacokinetic 
samples will be placed in a storage freezer at minus 20 degrees Centigrade or lower within 60 
minutes of blood draw. Samples will remain frozen until assayed. A more detailed description of 
plasma sample preparation requirements may be provided by the analytical laboratory. If such a 
description is provided, the method of sample preparation provided by the laboratory shall supersede 
those provided in this protocol and appropriate documentation shall be placed in the study master file. 
The samples will be transferred in two separate shipments to the analytical laboratory after 
completion of the study or at mutually agreed upon time points during the clinical conduct of the 
study. Primary samples shall be shipped separate from back-up samples. Prior to shipment, the 
samples will be appropriately packed in a Styrofoam cooler containing dry ice. Sufficient dry ice will 
be added to ensure that the samples will remain frozen for at least 24 hours for local shipments and 
for at least 72 hours for remote shipments. The shipment will be accompanied by documentation 
containing the following information: name of the study drug product, protocol number, number of 
subjects, and number of samples included in the shipment. All frozen pharmacokinetic samples will 
be transferred with accompanying documentation to: 
Worldwide Clinical Trials 
Early Phase Services/Bioanalytical Sciences, Inc. 
Attention: Ian David 
8609 Cross Park Drive 
Austin, Texas 78754 
Telephone: 512.834.7766 
Fax: 512.834.1165 


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5.6 
End-of-Study Procedures 
A brief physical examination, an ECG, and vital signs measurements (blood pressure, pulse rate, 
respiration rate, temperature, and pulse oximetry) will be performed on the day of study discharge. 
The vital signs measurements should be completed prior to the 24 hour blood collection. The ECG 
will be performed after subject has been in supine position for a minimum of 5 minutes. Blood will be 
collected for the same hematology and chemistry tests performed during screening. Adverse events 
and changes in concomitant medications will be assessed. When possible, end-of-study procedures 
will be performed in the event of a subject’s early termination from the study. 
5.7 
Safety Monitoring and Procedures 
A full set of vital signs will be measured at screening and at -0.5 hours pre-dose, at 2, 4, 6, 8, 12 and 
24 hours post-dose as given in Table 2. 
Table 2: Schedule of Vital Signs Measurements 
 
Time point 
Blood Pressure 
(mmHg) 
Pulse 
(Beats/min) 
Temperature 
(°C) 
Respiration rate 
(Breaths/min) 
Pulse oximetry 
(SpO2; %) 
Screening 
X 
X 
X 
X 
X 
-0.5 hours 
X 
X 
X 
X 
X 
2 hours post-dose 
X 
X
X 
X
4 hours post-dose 
X 
X
X 
X
8 hours post-dose 
X 
X
X 
X
12 house post-dose 
X 
X 
X 
X 
X 
24 hours post-dose 
X 
X 
X 
X 
X 
Electrocardiogram (Holter, provided by eResearch Technology, Inc.) will be monitored from pre-
dose until completion of 24 hours post dose, and additional vital signs measurements may be 
performed as deemed medically necessary by research personnel. All vital signs measurements will 
be taken after the subject has completed a minimum 3-minute sit.  
Subjects will be closely monitored during the confinement period in the research facility. Subjects 
will be instructed to inform the study physician and/or research personnel and/or parent of any 
adverse events (AEs) that occur at any time during the study. 
Procedures will be completed as specified in this protocol unless contraindicated due to a reported 
AE. 
Medical emergency personnel trained in advanced cardiac life support will be on site to monitor 
subjects during the confinement period in the research center. Emergency medical equipment 
including but not limited to intubation equipment and pulse oximetry shall be maintained on site to 
administer appropriate medical care should it be required. A physician will remain on site after each 
dose administration and will be available immediately. 
 
6 
ADVERSE EVENTS 
Subjects will be monitored for any adverse events (AEs) and Serious Adverse Events (SAEs) from 
the beginning of confinement until the end-of-study visit. The Investigator or a medically qualified 
designee will review each event. The Investigator or a Sub-Investigator will assess its relationship to 
the study drug. Each sign or symptom will be graded for severity, and the date and time of onset, 
cessation and resolution will be recorded. Treatment of any adverse reactions will be evaluated and 


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managed by a physician at the study site. All non-serious AEs will be reported on a regular basis or as 
specified by the Sponsor. Adverse events will be monitored and documented using MeDRA 
terminology.42 
6.1 
Definitions 
6.1.1 Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
An AE can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, without judgment to causality. An AE can 
arise from any use of the drug (eg, off-label, use in combinations with another drug) and from any 
route of administration, formulation, or dose, including an overdose. 
6.1.2 Life-Threatening Adverse Event/Life-Threatening Suspected Adverse Reaction 
A life-threatening AE/life-threatening suspected adverse reaction, in the view of either the 
Investigator or sponsor, places the patient or subject at immediate risk of death. It does not include an 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
6.1.3 Serious Adverse Event/Serious Suspected Adverse Reaction 
A Serious Adverse Events (SAE) or serious suspected adverse reaction, in the view of either the 
investigator or sponsor, results in any of the following outcomes: Death, a life-threatening AE, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
6.1.4 Unexpected Adverse Event/Unexpected Suspected Adverse Reaction 
An unexpected AE/unexpected suspected adverse reaction is an AE or suspected adverse reaction that 
is not listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application, as 
amended. 
6.2 
Serious Adverse Event Reporting 
The Investigator or designee will notify the appropriate sponsor contact immediately after the SAE 
detection, observation, or report of occurrence. The sponsor contact information for SAE reported is 
provided below: 
Akwete Lex Adjei, Ph.D. 
Executive Director, Product Development  
Rhodes Pharmaceuticals, L.P. 
498 Washington Street  


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Coventry, Rhode Island 02816  
Phone: 401-262-9408;  
Fax: 401-262-9403 
Email: akwete.adjei@pharma.com 
These SAE reports must contain the following information: 
1.
Study name/number
2.
Study drug
3.
Investigator details (name, phone, fax, e-mail)
4.
Subject number
5.
Subject initials
6.
Subject demographics
7.
MedWatch 3500 form
8.
Clinical event
i.
Description
ii.
Date of onset
iii.
Treatment (drug, dose, dosage form)
iv.
Adverse event relationship to study drug
v.
Action taken regarding study drug in direct relationship to the adverse event
9.
If the adverse event was fatal or life-threatening.
10. If hospitalized, hospital records.
11. Cause of death (whether or not the death was related to study drug)
12. Autopsy findings (if available)
Any new SAE that occurs beyond one month after the study period and is considered to be possibly 
related to the Investigational Medicinal Product (IMP) should be recorded and reported immediately 
to the Sponsor. 
The person responsible for the study shall take care that the study has been carried out in accordance 
with pharmacovigilance local regulations. 
All serious event reporting will adhere to 21 CFR 312.32 for IND drugs and 21 CFR 314.80 for 
marketed drugs (15-day alerts). The Institutional Review Board (IRB) will be notified of the alert 
reports per Food and Drug Administration (FDA) regulations. 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and treatment 
administered will be recorded on the case report form (CRF). 
6.3 
Relationship to Study Treatment 
The relationship between the AE and the investigational product will be determined by the 
Principal Investigator or Sub-Investigator on the basis of his/her clinical judgment and the 
following definitions: 
1= Related: 
The AE follows a reasonable temporal sequence from the study product administration, and cannot be 
reasonably explained by the subject’s clinical state or other factors (e.g., disease under study, 


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concurrent diseases, or concomitant medications). 
The AE follows a reasonable temporal sequence from the study product administration, and 
represents a known reaction to the drug under study or other drugs in its class, or is predicted by the 
known pharmacological properties of the drug. 
The AE resolves with discontinuation of the investigational product and/or recurs with rechallenge, if 
applicable. 
2 = Not Related: 
The AE does not follow a reasonable temporal sequence from study product administration, or can be 
reasonably explained by the subject’s clinical state or other factors (e.g., disease under study, 
concurrent diseases, and concomitant medications). 
 
7 
GENERAL CONSIDERATIONS 
7.1 
Basic Principles 
This research will be carried out in accordance with the protocol, the International Conference on 
Harmonisation (ICH), Guideline for Good Clinical Practice: Consolidated Guidance (E6), and 
applicable regulatory requirements(s) including clinical research guidelines established by the Basic 
Principles defined in the U.S. 21 CFR Parts 50, 56, and 312 and the principles enunciated in the 
Declaration of Helsinki (revised version Fortaleza 2013). 
7.2 
Protocol Approval 
The protocol, informed consent and assent must be approved by the IRB. 
7.3 
Institutional Review Board 
This protocol will be reviewed by an appropriate IRB and study enrollment will not commence until 
the Board has approved the protocol or a modification thereof. The Board is constituted and operates 
in accordance with the principles and requirements described in the U.S. Code of Federal Regulations 
(21 CFR Part 56). 
7.4 
Informed Consent Form and Assent 
Before implementation of the study, the investigator will provide the sponsor with a copy of the IRB 
approved consent form, printed on the investigator’s or institution's letterhead. All patients will be 
fully informed of the nature and purpose of the study and will give verbal assent and a parent or 
guardian will provide written consent prior to entry into the study. A copy of the consent form will be 
given to the parent or guardian and the original retained by the Investigator/site.  Parent or guardian 
will be informed of any significant new findings that could affect their decision that their child will 
remain in the study. 
7.5 
Investigator’s Brochure 
Prior to the start of the study the principal investigator will be provided with an Investigator’s 
Brochure (IB). The IB will be carefully reviewed by the investigator prior to patient enrolment. 
7.6 
Protocol Modifications 
Neither the investigator nor the sponsor will modify the protocol without first obtaining the 


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concurrence of the other. All changes must be submitted to the IRB. Protocol modifications that 
impact on patient safety or the validity of the study must be approved by the IRB and the FDA before 
implementation. 
7.7 
Qualified Investigator Undertaking 
Before initiation of the study, the investigator will supply the sponsor with a completed Qualified 
Investigator Undertaking. A curriculum vitae and current medical license will also be provided for all 
investigators and all co-investigators. 
 
7.8 
Indications for Subject Withdrawal 
Parent will be free to withdraw his/her children at any time for any reason, or they may be 
withdrawn if necessary, to protect their health and safety or the integrity of the study data. 
The final report will include reasons for withdrawals. In the event of an early termination, patient will 
undergo the procedures described in Section 5.6. If necessary, subjects will be followed up at the 
request of the Principal Investigator. 
If a subject experiences emesis within 2-4 hours of dosing (based on 2 times the Tmax of 
methylphenidate of approximately 1-2 hours), the subject will be discontinued from the study and 
his/her pharmacokinetic samples will not be analyzed. If emesis occurs after 4 hours, the subject will 
be retained in the study and his/her pharmacokinetic samples will be analyzed. 
7.9 
Termination of the Study 
The Principal Investigator reserves the right to terminate the study in the interest of subject safety and 
welfare. The Sponsor reserves the right to terminate the study at any time for administrative reasons. 
7.10 
Treatment of Outliers 
If anomalous pharmacokinetic results are noted for a subject, the pharmacokinetic data for the 
patients in question may be reviewed to determine if the patients is a statistical outlier. The outlier 
test will be performed using the Grubb’s Test (T Procedure) applied to the Test/Reference ratio for 
the relevant pharmacokinetic parameters, Cmax, AUClast, and AUCinf in particular. If the subject is 
determined to be a statistical outlier, the statistical analyses (e.g., ANOVA) will be performed with 
and without the outlier in the analysis data set. Both ANOVA results, i.e., without the outlier (primary 
analysis) and with the outlier (secondary analysis), will be reported. In the event of outliers, a redose 
challenge study will be conducted to either confirm or reject the outlier. 
7.11 
Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy of the 
informed consent document and Health Insurance Portability and Accountability Act (HIPAA) 
documents, completed CRFs (where applicable), drug accountability and retention records, and other 
study related documents will be retained in the permanent archives of the study site. These will be 
available for inspection at any time by the Sponsor or the FDA. Per 21 CFR 312, record retention for 
this study is required for a period of two years following the date on which this study agent is 
approved by the FDA for the marketing purposes that were the subject of this investigation; or, if no 
application is to be filed or if the application is not approved for such indication, until two years 
following the date on which the entire study (not merely the Investigator’s portion of the study, if it 


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involved more than one investigator) is completed, terminated, or discontinued, and the FDA is 
notified. 
Subject records will be kept private except when ordered by law. The following individuals will have 
access to study subject records: Principal Investigator and designees, study Sponsor, monitors, and 
auditors, the FDA, other government offices, and the IRB. 
7.12 
Trial Monitoring 
Sponsor personnel (or designees) will be responsible for monitoring the study to ensure compliance 
with the protocol and GCP. Compliance may be verified by one or more of the following methods: 
on-site visits, frequent communication with the Investigator, and/or review of CRFs and source 
documents. The Investigator agrees to permit such monitoring as well as audits or reviews by 
regulatory authorities and the IRB. 
7.13 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms agreed 
upon by the parties. 
7.14 
Quality Control and Quality Assurance Audits 
The raw data generated during the conduct of the study as well as reports will undergo a thorough 
Quality Control (QC) check and random Quality Assurance (QA) process for conformance to this 
protocol and all the governing Standard Operating Procedures (SOPs) by auditors from the QA 
departments of Worldwide Clinical Trials (WCT). The final report will contain a statement for quality 
assurance duly signed by a qualified representative of the Quality Assurance department. 
7.15 
Archiving 
All raw data generated during the clinical phase of this study, together with an original of this 
protocol, signed ICFs, and an original of the final report will be archived according to the ICH 
guideline for good clinical practice. 
7.16 
Confidentiality of Data 
Subject records will be kept private except when ordered by law. The following individuals will have 
access to study subject records: Principal Investigator and designees, study Sponsor, monitors, and 
auditors, FDA, other government offices, and the IRB. 
All reports and subject samples will be identified only by Study Identification Number and initials to 
maintain subject confidentiality. 
7.17 
Publication Policy 
Results of the study including all obtained data will be the property of the Sponsor of this study. For 
any publication pertaining to the data or results of study, a written approval of Sponsor will be 
obtained prior to communicating for publication and the manuscript will be sent for Sponsor’s 
approval, if the Sponsor asks to do so. 
7.18 
Investigator Responsibilities 
The Investigator will agree to conduct the study in accordance with the relevant, current protocol and 
to only make changes in a protocol after notifying the Sponsor, except when necessary to protect the 


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safety, rights, or welfare of subjects, and to comply with all other requirements regarding the 
obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312. 
 
8 
PHARMACOKINETIC ANALYSIS 
8.1 
Analytical Methodology 
Plasma samples will be analyzed for methylphenidate using a validated assay. The samples from all 
evaluable subjects completing the study will be analyzed. 
Incurred sample reproducibility will be performed and reported per WCT SOPs. 
8.2  
Pharmacokinetic Parameters 
Pharmacokinetic parameters for methylphenidate will be calculated using non-compartmental 
analysis. The pharmacokinetic parameters that will be determined are detailed in below 
 
Pharmacokinetic Parameter 
Definition 
Cmax 
Maximum observed plasma concentration
Cmax / Dose 
Dose normalized Cmax
AUC0-t 
Area under the plasma concentration-time curve from dosing to the 
final sample with a concentration greater than limit of quantitation 
(LOQ)
AUC0-t / Dose 
Dose normalized AUC0-t
AUC0-inf 
Area under the plasma concentration-time curve from dosing 
extrapolated to infinity. AUC0-inf is calculated as AUC0-t + Clast/Kel 
where Clast is the final sample with a concentration greater than LOQ 
and Kel is the terminal elimination rate constant 
AUC0-inf / Dose 
Dose normalized AUC0-inf
CL/F 
Apparent clearance
CL/F/Kg 
Weight normalized Apparent clearance
Vd/F 
Apparent volume of distribution
Vd/F/Kg 
Weight normalized Apparent volume of distribution 
tmax 
Time of maximum observed plasma concentration: Time to Cmax
t½  
Elimination half-life: 0.693/Kel
Kel 
Terminal elimination rate constant
Dose and weight normalized dose  Dose and weight normalized dose (mg/kg) 
AUC0-4 
Area under the plasma concentration-time curve from dosing to 4 
hours
AUC4-8 
Area under the plasma concentration-time curve from 4 hours to 8 
hours
AUC8-12 
Area under the plasma concentration-time curve from 8 hours to 12 
hours
F - Fraction of dose determined by bioavailability 
The maximum plasma concentration (Cmax) and time to Cmax (Tmax) will be taken directly from the 
data. The elimination rate constant, z, will be calculated as the negative of the slope of the terminal 
log-linear segment of the plasma concentration-time curve; the range of data to be used will be 
determined by visual inspection of a semi-logarithmic plot of concentration vs. time.  


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Elimination half-life (T½) will be calculated according to the following equation: T½ = 0.693 / λZ 
Area under the curve to the final sample with a concentration greater than the LOQ (AUClast) will be 
calculated using the linear trapezoidal method and extrapolated to infinity using: 
AUCinf = AUClast + Clast/ λZ 
Where Clast is the final concentration LOQ. 
Cmax and AUC will be dose normalized. Apparent clearance (Cls) and apparent volume of 
distribution will be reported 
Secondary pharmacokinetic endpoints will be the respective time to Cmax (tmax), the elimination 
half-life (t½), and the terminal elimination rate constant (Kel) will be calculated. 
All evaluable subjects will be included in the pharmacokinetic analysis. Pharmacokinetic 
calculations will be performed using appropriate software, e.g. Phoenix™ WinNonlin® (Version 
6.3, Pharsight Corporation) and/or SAS® (Version 9.3, SAS Institute Inc.). 
All the derived PK parameters described above will be listed.  The PK parameters will be 
summarized by dose groups. For AUC, Cmax, CL/F/kg, Vd/F/kg, CL/F, Vd/F and the 
normalized results, the following summary statistics will be calculated: median, maximum, 
minimum, arithmetic mean, standard deviation, CV, geometric mean, 95% confidence interval 
for the geometric mean, and standard deviation of loge transformed data.  For other parameters, 
median, maximum, minimum, arithmetic mean, and standard deviation will be calculated. 
Comparison of the PK parameters Cmax, AUC0-t, and AUC0-inf will be performed using an analysis of 
variance (ANOVA) model with dose group as the only factor in the model. The lowest dose group 
will be selected as the reference group and other dose groups will be compared to the reference group 
in a pairwise fashion. If the number of subjects in each dose group is too sparse, additional analyses 
with grouping certain dose levels together may be carried out. This decision will be based on 
subjects’ dosing records and will be made before database lock. 
The loge transformed normalized parameter will be used in the analyses 
8.3 
Statistical Analysis 
Comparison of the PK parameters Cmax, AUC0-t, and AUC0-inf will be performed using an analysis of 
variance (ANOVA) model with dose group as the only factor in the model. The lowest dose group 
will be selected as the reference group and other dose groups will be compared to the reference group 
in a pairwise fashion. If the number of subjects in each dose group is too sparse, additional analyses 
with grouping certain dose levels together may be carried out. This decision will be based on 
subjects’ dosing records and will be made before database lock. 
The loge transformed normalized parameter will be used in the analyses. The point estimate of the 
ratio of the dose normalized PK parameters with associated 90% confidence interval will be 
presented Statistical analyses will be performed using appropriate software, e.g. Phoenix™ 
WinNonlin® (Version 6.3, Pharsight Corporation) and SAS® (Version 9.3, SAS Institute Inc.). 
 
9 
FACILITIES 
ANALYTICAL LABORATORY 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, Inc. 


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8609 Cross Park Drive 
Austin, Texas 78754 
Phone: 512-834-7766 
 
10 
DRUG SUPPLIES 
Rhodes Pharmaceuticals or designee will supply sufficient quantities of the study drug to allow 
completion of this study. Study drug formulations methylphenidate 10, 15, 20, 30 and 40 mg capsule 
will be shipped to the clinical site pursuant to site SOPs. The lot numbers of the drugs along with the 
expiration dates (where available) will be recorded and copies of the Certificate of Analysis (where 
available) will be maintained on file. As methylphenidate is a scheduled drug it should always be 
locked and dispensed under strict supervision. 
Records will be maintained of the receipt and dispensation of the drugs supplied. At the conclusion of 
the study, any unused drug product will be stored as per FDA and DEA guidelines. 
 
11 
FINAL REPORT 
A final report (eCTD format) will be the responsibility of WCT and will signed and approved by 
the qualified Investigator. Data will be provided in CDISK format. 
12 
ADMINISTRATIVE ISSUES 
The Investigator is referred to the Aptensio XR® package insert, Investigator Brochure, or 
information provided during the study initiation visit, information provided by the study monitor, 
and ICH Guidelines for Good Clinical Practice for information regarding the study drug, details, or 
general considerations to be followed during the course of this study. 
 
 


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13 
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1. Shaywitz S, Shaywitz B. Diagnosis and management of attention deficit disorder: A pediatric 
perspective. Pediatr Clin North Am 1984; 31(2):429-457. 
2. Rutter M, Cox a, Tupling C, et al. Attainment and adjustment in two geographical areas? I. The 
prevalence of psychiatric disorder. British Journal of Psychiatry 1975; 126:493-509. 
3. Aman MG, Singh NN. Aberrant Behaviour Checklist. Canterbury, New Zealand, University of 
Canterbury 1983. 
4. Campbell M, Gonzalez NM, Silva RR. The pharmacologic treatment of conduct disorders and 
rage outbursts. Pediatric Psychopharmacology 1992; 15(1):69-85. 
5. Shukla VK, Otten N. Assessment of attention deficit/hyperactivity disorder therapy: A Canadian 
perspective. Ottawa: Canadian Coordinating Office for Health Technology Assessment 
(CCOHTA); 1999. 
6. Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder. NIH Consensus Statement 
1998 Nov 16-18; 16(2). 
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th 
ed.: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994: 78-85. 
8. Barkley R. Attention-Deficit Hyperactivity Disorder. Scientific American, 
9. Kazdin AE. Conduct disorders in childhood and adolescence. London, Sage Publications, 1987. 
10. Barr CL. Genetics of childhood disorders: xxii. ADHD, part 6: the dopamine D4 receptor gene. 
J Am Acad Child Adolesc Physchiatry 2001; 40: 118-121. 
11. Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M 
Dopaminergic System Genes in ADHD: Toward a Biological Hypothesis. 
Neuropsychopharmacology 2002; 27:607-19. 
12. Madras BK, Miller GM, Fischman AJ. The dopamine transporter: relevance to attention deficit 
hyperactivity disorder (ADHD). Behav. Brain Research 2002; 130:57-63. 
13. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ.  Dopamine 
transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999; 354: 
2132-2133. 
14. Krause K, Dresel SH, Krause J, and Kunch HF, Tatsch K. Increased striatal dopamine transporter 
in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as 
measured by single photon emission computed tomography. Neurosci Lett 2000; 285: 107-110. 
15. Kimko HC, Cross JT, Abernethy DR Pharmacokinetics and clinical effectiveness of 
methylphenidate. Clin Pharmacokinet. 1999;37(6):457–470. 
16. Ritalin® LA label 
17. Concerta® label 
18. Metadate® CD label 
19. Quillivant™ label 
20. Faraj BA, Ismaili ZH, Perel JM, Jenkins ML, Holtzman SG, Cucinell SA, Dayton PG. Metabolism 
and disposition of methylphenidate-14C: Studies in man and animals. J Pharmacol Exp Ther 1974; 


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191(3):535-547. 
20. Patrick KS, Kilts CD, Breese GR. Synthesis and pharmacology of hydroxylated metabolites of 
methyl-phenidate. J Med Chem 1981; 29:1237-40. 
21. Bartlett MF, Egger HP. Disposition and metabolism of methylphenidate in dog and man. Fed 
Proc 1972; 31:537. 
22. Redalieu E, Bartlett MF, Waldes LM, et al. A study of methylphenidate in man with respect to its 
major metabolite. Drug Metab Dispos 1982; 10:708-9. 
23. Chan YP, Swanson JM, Soldin SS, et al. Methylphenidate hydrochloride given with or before 
breakfast. II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 
1983; 72:56-9. 
24. Wargin W, Patrick K, Kilts C, et al. Pharmacokinetics of methylphenidate in man, rat and 
monkey. J Pharmacol Exp Ther 1983; 226:382-6. 
25. Modi NB, Lindemulder G, Gupta SK. Single- and multiple-dose pharmacokinetics of oral once-a- 
day osmotic Extended-Release OROSTM (methylphenidate HCl) formulation. J Clin Pharmacol 
2000; 40:379-88. 
26. Greenhill, LL Pharmacologic treatment of attention deficit hyperactivity disorder.  Psychiatr. 
Clin. North Am 1992; 15: 1-27. 
27. Hungund BL, Perel JM, Hurwic MJ, et al. Pharmacokinetics of methylphenidate in hyperkinetic 
children. J Clin Pharmacol. 1979; 8: 571-6. 
28. Elia, J., Borcherding, B. G., Potter, W. Z., Mefford, I. N., Rapoport, J. L., & Keysor, C. S. (1990). 
Stimulant drug treatment of hyperactivity: Biochemical correlates. Clinical Pharmacology & 
Therapeutics, 48, 57-66. 
29. Douglas VI, Barr RG, Amin K, O=Neill ME, Britton BG. Dosage effects and individual 
responsivity to methylphenidate in attention deficit disorder. J Child Psychol Psychiatry 1988; 
29(4):453-475. 
30. Canadian Paediatric Society, Mental Health Committee: Use of methylphenidate for attention 
deficit hyperactivity disorder. Can Med Assoc J 1990; 142(8):817-818. 
31. Douglas VI, Barr RG, O=Neill ME et al. Short-term effects of methylphenidate on the cognitive, 
learning and academic performance of children with attention deficit disorder in the laboratory 
and the classroom. J Child Psychol Psychiatry 1985; 27(2):191-211. 
32. Gualtieri CT, Hicks RE, Patrick K, et al. Clinical correlates of methylphenidate blood levels. Ther 
Drug Monit 1984; 6:379-392. 
33. Milberg RM, Rinhehart KL, Sprague RL, Sleator EK. A reproducible gas chromatographic mass 
spectrometric assay for low levels of methylphenidate and ritalinic acid in blood and urine. 
Biomed Mass Spectrum 1975; 2(1):2-8. 
34. Soldin SJ, Chan YM, Hill BM, Swanson JM. Liquid-chromatographic analysis for 
methylphenidate (Ritalin®) in serum. Clin Chem 1979; 25(3):401-404. 
35. Gualtieri CT, Wargin W, Kanoy R, Patrick K, Shen D, Youngblood W, Mueller 
RA, Breese GR. Clinical studies of methylphenidate serum levels in children and 
adults. J Amer Acad of Child Psych 1982; 21, 1:19-26. 
36. Brown RT, Borden KA, Clingerman SR. Adherence to methylphenidate therapy in a pediatric 
population. Psychopharmacol Bull 1985; 21(1):28-36. 


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37. Firestone P. Factors associated with children=s adherence to stimulant mediation. Am J 
Orthopsychiatry 1982; 52(3):447-457. 
38. Adjei A, Teuscher NS, Kupper RJ, Chang W-w, Greenhill L, Newcorn JH, Connor DF, Wigal S. 
Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads 
administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets 
(Ritalin®) in healthy adult volunteers. J Child Adolesc Psychopharmacol. (Accepted for 
publication). 
39. Adjei AL, Teuscher NS, Kupper RJ, Chang W-w, Greenhill L, Wigal S. Single dose 
pharmacokinetics of once-daily methylphenidate multilayer release (MLR) beads (Biphentin®, 
MPH-MLR) administered as capsule or sprinkles versus methylphenidate immediate-release 
tablets. J Pharm Pract. 2014;27(3):284. 
40. Wigal, SS, Greenhill LL, Nordbrock, E, Connor, DF, Kollins SH, Adjei A, Childress A, Stehli, A 
and Kupper, RJ. A  placebo-controlled double-blind study evaluating the time course of response to 
methylphenidate hydrochloride extended-release capsules in children with Attention-
Deficit/Hyperactivity Disorder. J. Child Adolesc Psychopharmacol. (Accepted for Publication). 
41. Medical Dictionary for Regulatory Activities version 13.1 (MeDRA MSSO, McLean, VA, USA). 
42. Birmaher B, Ehmann M, Axelson DA, Goldstein BI, Monk K, Kalas C, Kupfer D, Gill MK, 
Leibenluft E, Bridge J, Guyer A, Egger HL, Brent DA. Schedule for affective disorders and 
schizophrenia for school-age children (K-SADS-PL) for the assessment of preschool children--a 
preliminary psychometric study. J Psychiatr Res2009 Apr;43(7):680-6. 
43. McGoey KE, DuPaul G, Haley E, Shelton TL. Parent and Teacher Ratings of Attention- 
Deficit/Hyperactivity Disorder in Preshcool: The ADHD Rating Scale-IV Preschool Version. J 
Psychopathol Behav Assess. 2007;29:269-76. 
44. Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education and Welfare; 1976. 
45. Schaffer D, Gould M, Brasic J. A Children's Global Assessment Scale (CGAS). Archives of General 
Psychiatry;1983;40:1228-31 
 


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14 
APPENDICES 
14.1. K-SADS-PL 
The K-SADS-PL is a semi-structured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents according to DSM-III-R and DSM-IV 
criteria. Probes and objective criteria are provided to rate individual symptoms. Since ADHD 
criteria and impairment in preschool children is essentially the same in DSM-IV and DSM-5, the 
K-SADS-PL can be used to confirm the diagnosis. This interview has been used successfully to 
determine diagnoses in subjects aged 4 to 5 years.  The K-SADS-PL is administered at the 
Screening Visit.42 
14.2 
ADHD Rating Scale (ADHD-RS-IV) Preschool Version 
The ADHD-RS-IV Preschool Version will be used to determine ADHD symptomatology and 
severity.43   The Investigator or other designated, qualified individual will perform the assessment. 
ADHD-RS-IV Preschool Version is an 18 item adaptation of the original ADHD-RS-IV which is a 
measure of ADHD symptomatology.  For the Preschool Version symptom statements are modified to 
better capture behavior that is developmentally inappropriate for children aged 3-5 years.  The 
ADHD-RS-IV preschool version assessment is administered at the Day (-1) visit. 
14.3 
Clinical Global Impressions-Severity (CGI-S) Scale  
This scale provides a global rating of illness severity and improvement during the trial44.  The subject 
is rated relative to the clinician’s past experience with other patients who have the same diagnosis. 
The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses 
from 1 (normal) through to 7 (amongst the most severely ill patients). The CGI-S assessment is 
administered at the Day (-1) visit. 
14.4 
Children’s Global Assessment Scale (CGAS) 
This scale provides a global measure of functioning for children and adolescents.45  Each assessment 
is a single numerical rating from 1 – 100 (‘1’ represents subjects requiring constant (24 hour) 
supervision, while ‘100’ represents subjects displays superior functioning.)  The 100 point scale is 
arbitrarily subdivided into 10 subgroups that are used to classify the assessment (e.g. 100-91: superior 
functioning in all areas, 90-81: good functioning in all areas). The CGAS assessment is administered 
at the Day (-1) visit.