Conditions: Pain
Keywords: pharmacokinetics safety
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 97
Healthy volunteers: no

Brief summary:
The objective of this study is to characterize the pharmacokinetics and to evaluate the safety of single and multiple doses of Oxycodone Oral Solution in pediatric and adolescent subjects for postoperative pain.

Detailed description:
This is a Phase IV study to characterize the pharmacokinetics and to evaluate the safety of Oxycodone Oral Solution administered to pediatric and adolescent subjects for postoperative pain. It is an open label, multicenter study conducted at up to 10 sites. Subjects will be enrolled preoperatively up to 14 days before surgery with the expectation that they will require intravenous (IV) access after the surgery for at least 24 hours and postoperative analgesia with an opiate level medication. After dosing with Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 to 17, and a dose to be determined based on pharmacokinetic (PK) modeling from the interim analyses for subjects under age 2), subjects will be carefully monitored for safety. A total of 110 pediatric and adolescent male or female subjects will be enrolled, including a minimum of 20 subjects under age 2 (5 subjects ages 0 to \<2 months, 5 subjects ages 2 to \<6 months, and 10 subjects ages 6 months to \<2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to \<17 years. Subjects within each age group will be evenly distributed by age and gender.

An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years and 10 ages 13 to \<17 years have completed the study. The interim analysis will include PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and concomitant medications. The dose of Oxycodone Oral Solution that the subjects ages 6 months to \<2 years will receive will be based on PK modeling from the interim analysis.

An additional interim analysis will be run after at least half of the subjects aged 6 months to \<2 years have completed the study. The interim analysis will include PK, pulse oximetry readings, vital sign measurements, AEs and concomitant medications. The dose of Oxycodone Oral Solution that the subjects ages 0 to \<2 months and 2 months to \<6 months will receive will be based on PK modeling from the interim analysis.

The study will consist of a Screening period within 14 days of surgery; a predose check-in (Day -1); a treatment period after surgery (Day 1, Time Zero); and an End of Study assessment. The total duration of the study, excluding Screening, will be approximately 1 full day.

Eligible subjects who provide assent (7 to \<17 years old) and whose parent(s) or legal guardian(s) provide consent as required will have study assessments performed at Screening. Following surgery, subjects will receive standard care, including parenteral analgesia with a nonoxycodone, nonoxymorphone medication that will not interfere with the measurement or metabolism of oxycodone. At this time (during Day -1), they will have a predose check-in to have eligibility confirmed.

After subjects ages 2 to \<17 have been postoperatively cleared to transition to oral pain medication, Oxycodone Oral Solution will be administered at Time Zero of Day 1 in place of the standard analgesic medication. The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to \<17 age groups, who will be included in the first interim analysis, will only receive 1 dose of Oxycodone Oral Solution. Subjects in these age groups enrolled in the study after the interim analysis is completed may receive additional doses every 4-6 hours as needed. If pain control is inadequate with Oxycodone Oral Solution, the investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue medication for breakthrough pain after dosing. Use of other rescue pain medication is permissible in accordance with hospital pain management guidelines or facilities standard of care. Any rescue medications used will be provided by the study site pharmacy.

After subjects under age 2 have been postoperatively cleared to transition to oral pain medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero of Day 1 in place of the standard analgesic medication. The dose will be determined based on PK modeling from the interim analyses. If pain control is inadequate with Oxycodone Oral Solution, as indicated by a score of moderate to severe (4-10) on the FLACC, the subject will be given Fentanyl via Nurse-Controlled Analgesia (NCA). The Fentanyl will be provided by the study site pharmacy.

Subjects will undergo an End-of-Study assessment at least 24 hours after receiving the first dose of Oxycodone Oral Solution. At that time, if the study staff determines that it is safe to do so, subjects will be discharged from the study.

Safety will be assessed by monitoring AEs, clinical laboratory test results, vital sign measurements, temperature, pulse oximetry, and physical examination findings.

The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) will be used to measure pain prior to and 20, 40, 60, 90, 120, 180, and 240 minutes after the dose of Oxycodone Oral Solution in subjects under age 2. The FLACC will also be administered prior to the subject receiving each dose of Fentanyl.

Serial blood samples for PK analysis will be collected for the determination of plasma concentrations of oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) prior to the first dose (within 15 minutes of dosing); 5, 15, 30, and 60 minutes after dosing; and 2, 4, 6, 8, 12, and 24 hours after dosing. For subjects under age 2, serial blood samples for PK analysis will be collected prior to the first dose (within 15 minutes of dosing); 15, 30, and 60 minutes after dosing; and 2, 6, 12, and 24 hours after dosing.

Arms:
arm 1: Open label pharmacokinetic study of oxycodone.

Interventions: intervention 1: Oxycodone
Intervention descriptions: intervention 1: Pain

Protocol document:
Prot_SAP_000.pdf: 
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A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY 
OF OXYCODONE ORAL SOLUTION IN PEDIATRIC AND ADOLESCENT 
SUBJECTS 
 
PROTOCOL DATE: 
Version 7.0, Final 25 April 2013 
 
SPONSORED BY: 
VistaPharm, Inc. 
7256 Ulmerton Road 
Largo, FL 33771 
Phone:  (727) 530-1633 
 
 
Lehigh Valley Technologies, Inc. 
514 North 12th Street 
Allentown, PA 18102 
Phone:  (610) 782-9780 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
Cognitive Research Corporation
200 Central Avenue, Suite 1230 
St. Petersburg, FL 33701 
Phone: (727) 897-9000 
Fax: (727) 897-9009 
 
This study will be performed in compliance with Good Clinical Practices and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to 
the extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, 
or as required by law.  Persons to whom this information is disclosed should be informed that this 
information is confidential and may not be further disclosed without the express permission of 
VistaPharm, Inc. 
 


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1. PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Sponsor Contact Information 
Role in Study 
Name 
Address and  
Telephone Number 
Clinical Study Leader 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
Clinical Operations Leader 
Eva M. Kemper, 
MSHS 
Director, Clinical 
Projects  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-690-2667 
Physician 
Lawrence Blob, M.D.  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 410-262-1908 
24-hour Emergency Contact 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
 
Secondary Contact: 
Deborah Lees, R.N.  
Assistant Project 
Manager 
 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-943-8249 
 


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2. SYNOPSIS 
 
PRODUCT NAME 
OXYCODONE ORAL SOLUTION 
PROTOCOL NUMBER 
2012O004 
DEVELOPMENT PHASE 
PHASE IV 
PROTOCOL TITLE 
A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS 
AND SAFETY OF OXYCODONE ORAL SOLUTION IN PEDIATRIC 
AND ADOLESCENT SUBJECTS 
INDICATION 
Moderate to severe pain 
PRINCIPAL 
INVESTIGATOR 
This is a multicenter study.  The lead Principal Investigator will be: 
Senthilkumar Sadhasivam, M.D. 
Cincinnati Children’s Hospital Medical Center 
3333Burnet Avenue, MLC2001 
Cincinnati, OH 45229 
PLANNED STUDY 
SITES 
Up to 10 sites in the US. 
 
OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to 
evaluate the safety of single and multiple doses of Oxycodone Oral 
Solution in pediatric and adolescent subjects for postoperative pain.   
STUDY DESIGN 
This is a Phase IV study to characterize the pharmacokinetics and to 
evaluate the safety of Oxycodone Oral Solution administered to pediatric 
and adolescent subjects for postoperative pain.  It is an open-label, 
multicenter study conducted at up to 10 sites.  Subjects will be enrolled 
preoperatively up to 14 days before surgery with the expectation that they 
will require intravenous (IV) access after the surgery for at least 24 hours 
and postoperative analgesia with an opiate-level medication.  After dosing 
with Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 to 17, and a dose to be 
determined based on pharmacokinetic (PK) modeling from the interim 
analyses for subjects under age 2), subjects will be carefully monitored for 
safety.  A total of 110 pediatric and adolescent male or female subjects will 
be enrolled, including a minimum of 20 subjects under age 2 (5 subjects 
ages 0 to <2 months, 5 subjects ages 2 to <6 months, and 10 subjects ages 6 
months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 
13 to <17 years.  Subjects within each age group will be evenly distributed 
by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 
to 12 years and 10 ages 13 to <17 years have completed the study.  The 
interim analysis will include PK, pulse oximetry readings, vital sign 
measurements, adverse events (AEs) and concomitant medications.  The 
dose of Oxycodone Oral Solution that the subjects ages 6 months to <2 
years will receive will be based on PK modeling from the interim analysis. 
An additional interim analysis will be run after at least half of the subjects 
aged 6 months to <2 years have completed the study.  The interim analysis 
will include PK, pulse oximetry readings, vital sign measurements, AEs 
and concomitant medications.  The dose of Oxycodone Oral Solution that 


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the subjects ages 0 to <2 months and 2 months to <6 months will receive 
will be based on PK modeling from the interim analysis. 
The study will consist of a Screening period within 14 days of surgery; a 
predose check-in (Day −1); a treatment period after surgery (Day 1, 
Time Zero); and an End-of-Study assessment.  The total duration of the 
study, excluding Screening, will be approximately 1 full day. 
Eligible subjects who provide assent (7 to <17 years old) and whose 
parent(s) or legal guardian(s) provide consent as required will have study 
assessments performed at Screening.  Following surgery, subjects will 
receive standard care, including parenteral analgesia with a nonoxycodone, 
nonoxymorphone medication that will not interfere with the measurement 
or metabolism of oxycodone.  At this time (during Day −1), they will have 
a predose check-in to have eligibility confirmed.   
After subjects ages 2 to <17 have been postoperatively cleared to transition 
to oral pain medication, Oxycodone Oral Solution will be administered at 
Time Zero of Day 1 in place of the standard analgesic medication.  The first 
10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, who will 
be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  If pain control is inadequate with Oxycodone 
Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) 
every 4 hours as rescue medication for breakthrough pain after dosing.  Use 
of other rescue pain medication is permissible in accordance with hospital 
pain management guidelines or facilities standard of care.  Any rescue 
medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to 
oral pain medication, they will receive a single dose of Oxycodone Oral 
Solution at Time Zero of Day 1 in place of the standard analgesic 
medication.  The dose will be determined based on PK modeling from the 
interim analyses.  If pain control is inadequate with Oxycodone Oral 
Solution, as indicated by a score of moderate to severe (4-10) on the 
FLACC, the subject will be given Fentanyl via Nurse-Controlled Analgesia 
(NCA).  The Fentanyl will be provided by the study site pharmacy. 
Subjects will undergo an End-of-Study assessment at least 24 hours after 
receiving the first dose of Oxycodone Oral Solution.  At that time, if the 
study staff determines that it is safe to do so, subjects will be discharged 
from the study. 
Safety will be assessed by monitoring AEs, clinical laboratory test results, 
vital sign measurements, temperature, pulse oximetry, and physical 
examination findings. 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) will be 
used to measure pain prior to and 20, 40, 60, 90, 120, 180, and 240 minutes 
after the dose of Oxycodone Oral Solution in subjects under age 2.  The 
FLACC will also be administered prior to the subject receiving each dose 
of Fentanyl. 
Serial blood samples for PK analysis will be collected for the determination 
of plasma concentrations of oxycodone and its metabolites (noroxycodone, 
oxymorphone and noroxymorphone) prior to the first dose (within 
15 minutes of dosing); 5, 15, 30, and 60 minutes after dosing; and 2, 4, 6, 8, 
12, and 24 hours after dosing. For subjects under age 2, serial blood 


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samples for PK analysis will be collected prior to the first dose (within 15 
minutes of dosing); 15, 30, and 60 minutes after dosing; and 2, 6, 12, and 
24 hours after dosing. 
PLANNED NUMBER OF 
SUBJECTS 
A total of 110 subjects, including a minimum of 20 subjects under age 2, 30 
ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to <17 years, are 
planned for this study to ensure adequate evaluation of the safety and PK 
profiles of Oxycodone Oral Solution. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria  
A subject will be eligible for inclusion in the study if he or she meets the 
following criteria: 
1. Is male or female <17 years of age at the time of dosing. 
2. Subject 2 to <17 years of age, be in at least the 25% for weight 
according to the Center for Disease Control pediatric growth charts 
and weighs at least 28 lb at the time of dosing with study drug. 
3. Is generally healthy as documented by medical history (except for the 
condition for which the procedure is being performed); physical 
examination (including, but not limited to, the cardiovascular, 
gastrointestinal, respiratory, and central nervous systems); vital sign 
assessments; 12-lead electrocardiograms; clinical laboratory 
assessments; and general observations.  Has a negative serum 
pregnancy test at Screening and predose check-in for females of 
childbearing potential. 
4. Is an outpatient for a surgical procedure and is expected to remain 
hospitalized for at least 24 hours after dosing with study drug. 
5. Is anticipated to have postsurgical pain requiring a parenteral 
analgesic regimen using a short-acting opioid analgesic and is 
anticipated to be switched to an oral opioid for at least 1 dose 
(according to institution standard of care). 
6. Has an indwelling access catheter for blood sampling. 
7. Agrees to comply with all protocol requirements.  If not old enough, 
the legally responsible parent(s) or legal guardian(s) must agree to 
comply with all protocol requirements. 
8. Has been informed of the nature of the study and informed consent 
and assent (as appropriate) have been obtained from the legally 
responsible parent(s) or legal guardian(s) and the subject, 
respectively, in accordance with institutional review board 
requirements. 
Exclusion criteria  
A subject will be excluded from the study if he or she meets the following 
criteria: 
1. Has the presence or history of a clinically significant disorder 
involving the cardiovascular, respiratory, renal, gastrointestinal, 
immunologic, hematologic, endocrine, or neurologic system(s) or 
psychiatric disease (except for the condition for which the procedure 
is being performed) as determined by the clinical investigator. 
2. Has any clinical laboratory test result outside the normal range. 
3. Has a positive test result for hepatitis B surface antigen, hepatitis C 
antibody, or human immunodeficiency virus antibody. 


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4. Had a clinically significant illness, except for the condition for which 
the procedure is being performed, in the 28 days before dosing with 
study drug as determined by the clinical investigator. 
5. Is a lactating or breastfeeding female. 
6. Uses any medication known to be an inhibitor or inducer of CYP3A4 
within 14 days (for inhibitors such as the azole-antifungal agents 
voriconazole and ketoconazole, macrolide antibiotics such as 
erythromycin, and protease inhibitors such as ritonavir) or 28 days 
(for inducers such as rifampin, carbamazepine, and phenytoin) of 
dosing with study drug. Use of all other prescription medications, 
except required pre-op medications and birth control, is prohibited 
within 3 days of dosing with study drug.  Use of any over-the-counter 
medications (including herbal or dietary supplements and therapeutic 
doses of vitamins), except for required pre-op medications, is 
prohibited within 24 hours of dosing with study drug, with the 
exception of topical spermicide.  Use of St. John’s wort is prohibited 
from 28 days before dosing until 14 days after dosing.  Standard daily 
dose multivitamins (nontherapeutic doses) may be taken until 
enrollment into the study but will be restricted during the study. 
7. Consumes alcohol-, caffeine-, or xanthine-containing products within 
48 hours before dosing and during periods when blood samples are 
collected. 
8. Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-
containing products within 14 days of dosing.  Fruit juices, with the 
exception of apple and grape, will be prohibited during the study. 
9. Is a smoker or has used nicotine or nicotine-containing products 
within 30 days of dosing. 
10. Has a history of alcohol or drug addiction or abuse within the last 
year. 
11. Subject 2 to <17 years of age, has a positive urine test result for drugs 
of abuse (amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, and benzodiazepines) or alcohol 
at Screening (not required for subjects less than 2 years of age). 
12. Donated blood within 28 days or plasma within 14 days of dosing or 
plans to donate them within 4 weeks after completing the study. 
13. Has a history of relevant drug allergies, food allergies, or both 
(i.e., allergy to oxycodone, allergy to related drugs, or any significant 
food allergy that could interfere with the study). 
14. Is intolerant to direct venipuncture. 
15. Received an investigational drug within 28 days of dosing. 
16. Has taken oxycodone or oxymorphone within the 48 hours before 
anticipated dosing with study drug. 
17. Is not suitable for entry into the study in the opinion of the 
investigator. 
INVESTIGATIONAL 
PRODUCT 
Oxycodone Oral Solution provided by VistaPharm, Inc., supplied in 
500-mL bottles.  Oxycodone Oral Solution contains 4.5 mg of oxycodone 
free base per 5 mL (5 mg oxycodone HCl/5 ml) and the following inactive 
ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid anhydrous 
US Pharmacopeia (USP), glycerin natural USP, sorbitol solution 70% USP, 


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FD&C Red #40 , raspberry flavor, and water. 
TREATMENT REGIMEN 
Each subject in the 2 to 6, 7 to 12 and 13 to <17 age groups will receive a 
dose of Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to 17) in place of the 
standard analgesic dose after being postoperatively cleared to transition to 
oral pain medication.  The first 10 subjects in each of these age groups, 
who will be included in the first interim analysis, will only receive 1 dose 
of Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  Each subject under age 2 will receive a single 
dose of Oxycodone Oral Solution.  The dose will be determined based on 
PK modeling from the interim analyses.  Oxycodone Oral Solution will be 
administered with an oral medication syringe. 
CRITERIA FOR 
EVALUATION 
Pharmacokinetic endpoints: 
• 
Area under the plasma concentration versus time curve from 
Time Zero to the last measurable concentration (AUC0-t) 
• 
Area under the plasma concentration versus time curve from 
Time Zero to infinity (AUC0-inf) 
• 
Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• 
Maximum measured plasma concentration (Cmax) 
• 
Time of the maximum measured plasma concentration (Tmax) 
• 
Apparent first-order terminal elimination rate constant (Kel) 
• 
Apparent first-order terminal elimination half-life (t1/2) 
• 
Apparent clearance (CL/F) 
• 
Volume of distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
Safety endpoints: 
Safety will be assessed by the monitoring and recording of AEs; clinical 
laboratory results (including hematology, serum chemistry, and urinalysis); 
vital sign measurements (systolic and diastolic blood pressures, heart rate, 
and respiratory rate); temperature; pulse oximetry; and physical 
examination findings. 
 Exploratory Study Endpoints: 
Analgesic sparing will be the surrogate efficacy endpoint in children under 
age 2.The Total FLACC Score will be an exploratory endpoint in children 
under age 2. 
STATISTICAL 
METHODS 
Analysis Populations 
PK Population: the PK population will consist of all subjects who receive 
study drug and have at least 1 measureable plasma concentration. 
Safety Population: the safety population will consist of all subjects who 
receive study drug. 
Subject Characteristics and Disposition 
For categorical variables, frequencies and percentages will be presented.  
Continuous variables will be summarized using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized.  The 


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number of subjects who enroll in the study and the number and percentage 
of subjects who complete the study will be presented.  The frequency and 
percentage of subjects who withdraw or discontinue from the study, along 
with the reason for withdrawal or discontinuation, will also be summarized. 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and 
noroxymorphone) plasma concentrations will be listed and summarized.  
Each subject’s oxycodone plasma concentrations will be graphed by using 
both a normal scale y-axis and a logarithmic scale y-axis.  Mean oxycodone 
plasma concentrations will also be graphed using scheduled elapsed 
sampling times for both the normal and logarithmic scale y-axis. 
Pharmacokinetic parameters will be listed for each subject and 
summarized.  Key PK parameters will be contrasted with adult values from 
the literature. 
Other PK analyses may be performed as appropriate. 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities 
and will be summarized overall.  Adverse events will also be summarized 
by severity and relationship to study drug.  Serious AEs and AEs leading to 
discontinuation of study drug will also be summarized. 
Actual values and changes from Baseline for clinical laboratory results, 
pulse oximetry, and vital sign measurements will be summarized at each 
time point using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) or shift tables where appropriate.  Physical 
examination findings will be presented in a listing. 
  
SAMPLE SIZE 
DETERMINATION 
The evaluable sample size for this study is powered to target a 
95% confidence interval within 60% and 140% of the geometric mean 
estimates of clearance and volume of distribution for oxycodone with at 
least 80% power. 
Because of an anticipated dropout rate of 33%, a recruited sample size of 
30 subjects is considered sufficient to ensure 20 evaluable subjects to assess 
the PK profiles of Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, 
the trial will enroll 110 subjects to gather adequate safety information in 
the pediatric/adolescent patient population. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods will be as 
follows: 
Screening is up to 14 days. 
The total study duration for each subject is 1 full day, excluding Screening. 
The maximum treatment duration for each subject is 1 full day. 


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3. TABLE OF CONTENTS 
 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................9 
3.1 
List of Tables .....................................................................................................12 
4. 
LIST OF ABBREVIATIONS.....................................................................................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1 
Background and Rationale ................................................................................15 
5.1.1 Indication and Usage .............................................................................15 
5.1.2 Description ............................................................................................15 
5.1.3 Pharmacodynamics ................................................................................16 
5.1.4 Pharmacokinetics ...................................................................................16 
5.1.4.1 
Absorption .................................................................................16 
5.1.4.2 
Distribution ...............................................................................16 
5.1.4.3 
Metabolism ................................................................................17 
5.1.4.4 
Elimination ................................................................................17 
5.1.5 Clinical Experience ...............................................................................17 
5.1.6 Study Rationale .....................................................................................17 
5.2 
Summary of Potential Risks and Benefits .........................................................17 
5.2.1 Potential Risks .......................................................................................17 
5.2.2 Benefits ..................................................................................................18 
6. 
OBJECTIVE ...............................................................................................................19 
7. 
STUDY DESIGN .......................................................................................................19 
7.1 
Overall Study Design and Plan .........................................................................19 
7.2 
Discussion of Study Design ..............................................................................20 
7.3 
Study Sites .........................................................................................................21 
7.4 
Point of Contact .................................................................................................21 
8. 
SUBJECT POPULATION .........................................................................................21 
8.1 
Selection of Study Population ...........................................................................21 
8.1.1 Inclusion Criteria ...................................................................................21 
8.1.2 Exclusion Criteria ..................................................................................22 
8.2 
Removal of Subjects from Therapy or Assessment ..........................................23 
9. 
STUDY TREATMENTS............................................................................................24 
9.1 
Method of Assigning Subjects to Treatment Groups ........................................24 


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9.1.1 Under Age 2 ..........................................................................................24 
9.1.2 Ages 2 to <17 ........................................................................................24 
9.2 
Identification of Investigational Products .........................................................24 
9.3 
Treatment Administered ....................................................................................24 
9.3.1 Under Age 2 ..........................................................................................24 
9.3.2 Ages 2 to <17 ........................................................................................24 
9.4 
Storage ...............................................................................................................25 
9.5 
Labeling .............................................................................................................25 
9.6 
Drug Accountability ..........................................................................................25 
9.7 
Blinding and Unblinding Treatment Assignment .............................................25 
9.8 
Selection of Dose in the Study ..........................................................................25 
9.9 
Selection of Timing of Dose for Each Subject ..................................................26 
9.10 Treatment Compliance ......................................................................................26 
9.11 Permitted and Prohibited Therapies ..................................................................26 
9.11.1 Permitted Therapies ...............................................................................26 
9.11.2 Prohibited Therapies ..............................................................................27 
9.12 Rescue Medication ............................................................................................27 
10. STUDY PROCEDURES ............................................................................................28 
10.1 Screening (Day −14 to Day −1) ........................................................................28 
10.2 Predose Check-in (Day −1) ...............................................................................28 
10.3 Open-Label Treatment (Day 1, After Surgery) .................................................28 
10.4 End-of-Study/Early Discontinuation .................................................................30 
11. STUDY ASSESSMENTS ..........................................................................................31 
11.1 Pharmacokinetics ...............................................................................................31 
11.1.1 Sample Collection .................................................................................31 
11.1.2 Blood Volumes ......................................................................................32 
11.1.3 Sample Processing .................................................................................32 
11.1.4 Transport of Samples .............................................................................33 
11.1.5 Analytical Procedures ............................................................................33 
11.1.5.1 Bioanalytical Sample Analyses .................................................33 
11.1.5.2 Bioanalytical Methodology .......................................................33 
11.2 Safety .................................................................................................................34 
11.2.1 Adverse Events ......................................................................................34 
11.2.1.1 Adverse Event Definitions ........................................................34 
11.2.1.2 Eliciting and Documenting Adverse Events .............................35 
11.2.1.3 Reporting Adverse Events.........................................................35 


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11.2.1.4 Follow-up of Adverse Events....................................................38 
11.2.2 Laboratory Safety Assessments .............................................................39 
11.2.3 Vital Signs .............................................................................................39 
11.2.4 Pulse Oximetry ......................................................................................39 
11.2.5 Electrocardiogram .................................................................................39 
11.2.6 Physical Examination ............................................................................39 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) ..........................40 
12. STATISTICAL METHODS .......................................................................................40 
12.1 General Considerations .....................................................................................40 
12.2 Analysis Populations .........................................................................................40 
12.3 Statistical Analyses ............................................................................................40 
12.3.1 Subject Disposition and Demographic Characteristics .........................40 
12.3.2 Pharmacokinetic Analyses ....................................................................41 
12.3.3 Safety Analyses .....................................................................................41 
12.3.4 Exploratory Analyses ............................................................................41 
12.3.5 Interim Analyses ....................................................................................41 
12.4 Sample Size Determination ...............................................................................42 
13. STUDY CONDUCT ...................................................................................................42 
13.1 Sponsor and Investigator Responsibilities ........................................................42 
13.1.1 Sponsor Responsibilities .......................................................................42 
13.1.2 Investigator Responsibilities .................................................................42 
13.2 Site Initiation .....................................................................................................43 
13.3 Screen Failures ..................................................................................................44 
13.4 Study Documents ..............................................................................................44 
13.4.1 Good Clinical Practice Documents .......................................................44 
13.4.2 Case Report Forms ................................................................................44 
13.4.3 Source Documents .................................................................................45 
13.5 Data Quality Control .........................................................................................45 
13.5.1 Monitoring Procedures ..........................................................................45 
13.5.2 Data Management ..................................................................................46 
13.5.3 Quality Assurance/Audit .......................................................................46 
13.6 Study Termination .............................................................................................47 
13.6.1 Regular Study Termination ...................................................................47 
13.6.2 Premature Study Termination ...............................................................47 
13.7 Study Site Closure .............................................................................................47 
13.7.1 Record Retention ...................................................................................47 


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13.7.2 Sample Retention ..................................................................................48 
13.8 Changes to the Protocol .....................................................................................48 
13.9 Use of Information and Publication ..................................................................48 
14. FINAL CLINICAL STUDY REPORT ......................................................................49 
15. ETHICAL AND LEGAL CONSIDERATIONS ........................................................49 
15.1 Declaration of Helsinki and Good Clinical Practice .........................................49 
15.2 Subject Information and Informed Consent ......................................................49 
15.3 Approval by Institutional Review Board ...........................................................49 
16. REFERENCES ...........................................................................................................51 
17. ATTACHMENTS .......................................................................................................54 
17.1 Schedule of Events ............................................................................................54 
17.2 Treatment Day Procedures ................................................................................56 
17.3 Investigator’s Agreement ..................................................................................58 
17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) ...............................59 
18. APPENDICES ............................................................................................................60 
A. 
Address List .......................................................................................................61 
18.1.1 Sponsors ................................................................................................61 
18.1.2 Clinical Research Organization .............................................................61 
B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information ............................................................62 
 
3.1 
List of Tables 
Table 1: 
Sponsor Contact Information ..................................................................2 
Table 2: 
Schedule of Events ................................................................................54 
Table 3: 
Treatment Day Procedures ....................................................................56 


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4. LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AUC 
Area under the curve 
AUC0-inf 
Area under the concentration-time curve from Time Zero to infinity 
AUC0-t 
Area under the concentration-time curve from Time Zero to the last 
measurable concentration 
Cmax  
Observed maximum plasma concentration 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG  
Electrocardiogram 
EDC 
Electronic data capture 
FDA  
Food and Drug Administration 
FLACC 
Face, Legs, Activity, Cry, Consolability Scale 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonisation 
IRB  
Institutional review board 
ITT 
Intention-to-Treat Population 
IV 
Intravenous 
Kel 
Elimination rate constant  
kg 
Kilogram 
L 
Liter 
lbs 
Pounds 
mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
NCA 
Nurse-Controlled Analgesia 
PK 
Pharmacokinetic 
RPM 
Revolutions per minute 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
Standard of care 


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t1/2 
Apparent elimination half-life 
TBV 
Total blood volume 
Tmax 
Time of maximum concentration 
USP 
United States Pharmacopeia 
 


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5. INTRODUCTION 
5.1 
Background and Rationale 
5.1.1 
Indication and Usage 
Oxycodone (4, 5α-epoxy-14-hydroxy-3-methoxy-17methylmorphinan-6-one 
hydrochloride) is a semisynthetic opioid that has been in clinical use since 1917 and 
approved for use in the US since 1950.  Developed by VistaPharm, Inc., oxycodone 
hydrochloride (HCl) US Pharmacopeia (USP) oral solution, 5 mg per 5 mL, is an 
immediate-release oral formulation of oxycodone hydrochloride indicated for the 
management of moderate to severe acute and chronic pain where the use of an opioid 
analgesic is appropriate.  This product was approved by the Food and Drug 
Administration (FDA) on January 12, 2012 (application New Drug Application 201194).  
In addition, Lehigh Valley Technologies, Inc. has developed Oxycodone Hydrochloride 
Oral Solution available as a 100 mg/5 mL (20 mg/mL) concentration which is indicated 
for use in opioid-tolerant patients only. This product was approved by the Food and Drug 
Administration (FDA) on October 20, 2010 (application New Drug Application 200535). 
The results of the study described with the current protocol will be utilized to meet 
regulatory requirements for both VistaPharm, Inc. and Lehigh Valley Technologies, Inc.    
Oxycodone HCl is currently available in the US in a number of other forms and 
combinations.  Oxycodone is a Schedule II controlled substance. The VistaPharm, Inc., 
oxycodone hydrochloride (HCl) (USP) oral solution, 5 mg per 5 mL, will be utilized for 
the purposes of this protocol. 
5.1.2 
Description 
Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium 
alkaloid thebaine.  Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is 
considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). 
Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-
17methylmorphinan-6-one hydrochloride and has the following structural formula: 
 


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5.1.3 
Pharmacodynamics 
Oxycodone is a semisynthetic narcotic with multiple actions qualitatively similar to those 
of morphine; the most prominent of these involve the central nervous system and organs 
composed of smooth muscle.  The principal actions of therapeutic value of oxycodone are 
analgesia and sedation. 
Oxycodone is similar to codeine and methadone in that it retains at least one-half of its 
analgesic activity when administered orally. 
Additional detailed information on the pharmacodynamic properties of oxycodone 
hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the Approved Label 
and Full Prescribing Information (Appendix B). 
5.1.4 
Pharmacokinetics 
5.1.4.1 Absorption 
About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in 
comparison with a parenteral dose.  This high oral bioavailability (compared to other oral 
opioids) is due to lower presystemic metabolism, first-pass metabolism, or both of 
oxycodone. 
A single-dose food effect study was conducted in normal adult volunteers using the 
5 mg/5 mL solution.  The concurrent intake of a high fat meal was shown to enhance the 
extent (a 27% increase in the area under the plasma concentration versus time curve 
[AUC]) but not the rate of oxycodone absorption from the oral solution.  In addition, food 
caused a delay in the time of maximum concentration (Tmax) (1.25 to 2.54 hours). 
5.1.4.2 Distribution 
Following intravenous (IV) administration, the volume of distribution for oxycodone was 
2.6 L/kg.  Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%.  
Oxycodone has been found in breast milk. 


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5.1.4.3 Metabolism 
Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, 
and their glucuronides.  The major circulating metabolite is noroxycodone with an AUC 
ratio of 0.6 relative to that of oxycodone.  Oxymorphone is present in the plasma only in 
low concentrations.  The analgesic activity profile of other metabolites is not known at 
present. 
The formation of oxymorphone but not noroxycodone is mediated by CYP2D6 and as 
such its formation can, in theory, be affected by other drugs. 
5.1.4.4 Elimination 
Oxycodone and its metabolites are excreted primarily via the kidney.  The amounts 
measured in the urine have been reported as follows:  up to 19% was reported for free 
oxycodone; up to 50% was reported for conjugated oxycodone; 0% was reported for free 
oxymorphone; no greater than 14% was reported for conjugated oxymorphone; and both 
free and conjugated noroxycodone have been found in the urine but not quantified.  The 
total plasma clearance was 0.8 L/min for adults. 
Additional detailed information on the physical, chemical, and pharmaceutical properties 
of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the 
Approved Label and Full Prescribing Information (Appendix B). 
5.1.5 
Clinical Experience 
Oxycodone hydrochloride USP oral solution has been studied in adult populations, with a 
focus on pharmacokinetics, safety, and tolerability.  A total of 4 clinical pharmacokinetic 
(PK) and bioavailability studies have been conducted to support the development and 
labeling of oxycodone hydrochloride USP oral solution. 
In addition, there are a number of published studies in the medical literature that report on 
the pharmacokinetics of oxycodone in clinical and nonclinical settings, in a variety of 
doses and routes of administration.1-19 
5.1.6 
Study Rationale 
Despite published studies on dosing and pharmacokinetics in pediatric populations,20-25 
oxycodone has never received an official indication for use in children.  Pursuant to the 
Pediatric Research Equity Act (21 USC 355c), the FDA has requested that VistaPharm, 
Inc. and Lehigh Valley Technologies, Inc. conduct a postapproval and postmarketing 
(Phase IV) PK and safety study in subjects < 17 years of age. 
5.2 
Summary of Potential Risks and Benefits 
5.2.1 
Potential Risks 
The most frequently observed adverse events (AEs) reported with oxycodone include 
light headedness, dizziness, sedation, nausea, and vomiting.  These effects seem to be 
more prominent in subjects who can walk than in subjects who cannot walk, and some of 


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these adverse reactions may be alleviated if the subject lies down.  Other AEs include 
euphoria, dysphoria, constipation, skin rash, and pruritus. 
Additional detailed information on potential AEs and on specific warnings and 
precautions with the use of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, 
can be found in the Approved Label and Full Prescribing Information (Appendix B). 
Given that some of the subjects will be infants and young children, the effect of multiple 
blood draws can be considered a potential risk or adverse situation.  A published review 
of the safe limits of blood sample volumes in child health research suggests that existing 
guidelines specify limits ranging from 1% to 5% of total blood volume (TBV) over 
24 hours.  However, the limited available evidence that includes findings from 
nonrandomized studies shows a minimal risk with one-off sampling of up to 5% of 
TBV.26 
For subjects 2 <17 years of age, this protocol specifies a maximum of 11 serial blood 
samples of 0.5 mL each for a total of 5.5 mL, plus 2.5 mL each for standard clinical 
chemistry and hematology tests at Screening and End of Study.  In addition, up to 10 mL 
will be allotted as discard volume for the 11 PK samples and the final laboratory testing 
drawn through the indwelling catheter.  Existing blood draw guidelines for pediatric 
research suggest minimal risk is between 3% and 5% of total blood volume (TBV) over 
24 hours or on a single draw and TBV is generally estimated at 75-80 mL/kg.  For the 
smallest child permitted per protocol, 2 to <17 years of age (weight: 28 lbs or 12.7 kg), 
the TBV would be estimated at 952.5 ml. The maximum safe volume drawn would 
therefore be between 28 and 47 mL, based on minimal risk at 3-5% TBV over 24 hours.  
The required 10.5 mL plus up to 10 mL of discard volume, or a cumulative volume of 
20.5 mL, is well under the 3-5% of TBV guideline for the smallest eligible participant 
using the smallest estimation of TBV. 26 
For the child less than 2 years of age, there is a maximum of 8 serial blood samples of 0.5 
mL each for a total of 4.0 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 9 mL is under the 3-5% of 
TBV guideline. 
5.2.2 
Benefits 
The size of the test dose (0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 
0.07 mg/kg for ages 13 to 17, and a dose to be determined based on PK modeling from 
the interim analyses for subjects under age 2) is designed to provide adequate analgesia 
for moderate to severe pain in substituting for the routinely prescribed postoperative pain 
regimen according to the custom of the attending physician and the institutional standard 
of care (SOC). 
No other benefit is anticipated or expected for subjects participating in this study. 


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6. OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to evaluate the 
safety of single and multiple doses of Oxycodone Oral Solution in pediatric and 
adolescent subjects.   
7. STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a Phase IV study to characterize the pharmacokinetics and to evaluate the safety 
of Oxycodone Oral Solution administered to pediatric and adolescent subjects following 
a surgical procedure.  It is an open-label, multicenter study conducted at up to 10 sites.  
Subjects will be enrolled preoperatively up to 14 days before surgery with the expectation 
that they will require IV access after the surgery for at least 24 hours and postoperative 
analgesia with an opiate-level medication.  After dosing with Oxycodone Oral Solution 
(0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 
to 17, and a dose to be determined based on PK modeling from the interim analyses for 
subjects under age 2), subjects will be carefully monitored for safety.  A total of 
110 pediatric and adolescent male or female subjects will be enrolled, including a 
minimum of 20 subjects under age 2 (5 subjects ages 0 to <2 months, 5 subjects ages 2 to 
<6 months, and 10 subjects ages 6 months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 
12 years and 30 ages 13 to <17 years.  Subjects within each age group will be evenly 
distributed by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects under 
age 2 will receive will be based on PK modeling from the interim analysis.  
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on PK modeling from the interim analysis. 
The study will consist of a Screening period within 14 days of surgery; a predose 
check-in (Day −1); a treatment period after surgery (Day 1, Time Zero); and an 
End-of-Study assessment.  The total duration of the study, excluding Screening, will be 
approximately 1 full day. 
Eligible subjects who provide assent (7 to <17 years old) and whose parent(s) or legal 
guardian(s) provide consent as required will have study assessments performed at 
Screening.  Following surgery, subjects will receive standard care, including parenteral 
analgesia with a nonoxycodone, nonoxymorphone medication that will not interfere with 
the measurement or metabolism of oxycodone.  At this time (during Day −1), they will 
have a predose check-in to have eligibility confirmed.   


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After subjects ages 2 to <17 years have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of Day 1 in 
place of the standard analgesic medication.  The first 10 subjects in each of the 2 to 6, 7 
to 12 and 13 to <17 age groups, who will be included in the first interim analysis, will 
only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age groups enrolled in 
the study after the interim analysis is completed may receive additional doses every 4-6 
hours as needed.  If pain control is inadequate with Oxycodone Oral Solution, the 
investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 6 hours or an IV 
dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue medication for 
breakthrough pain after dosing.  Use of other rescue pain medication is permissible in 
accordance with hospital pain management guidelines or facilities standard of care.  Any 
rescue medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero of 
Day 1 in place of the standard analgesic medication.  The dose will be determined based 
on PK modeling from the interim analyses.  If pain control is inadequate with Oxycodone 
Oral Solution, as indicated by a score of moderate to severe (4-10) on the FLACC, the 
subject will be given Fentanyl via NCA.  The Fentanyl will be provided by the study site 
pharmacy. 
Water, Gatorade, Powerade, Pedialite, or Popsicles will be allowed for the first hour (1 
hour) following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study.  
Subjects will undergo an End-of-Study assessment at least 24 hours after dosing with 
Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do 
so, subjects will be discharged from the study.  Subjects who discontinue the study for 
any reason will not be replaced. 
Safety will be assessed, between time 0 and 24 hours post first study medication 
administration, by monitoring AEs, clinical laboratory test results, vital sign 
measurements, temperature, pulse oximetry, and physical examination findings. 
The FLACC will be used to measure pain prior to  and 20, 40, 60, 90, 120, 180, and 240 
minutes after the dose of Oxycodone Oral Solution in subjects under 2 years of age.  The 
FLACC will also be administered prior to the subject receiving each dose of Fentanyl. 
For subjects 2 to <17 years of age, serial blood samples for PK analysis will be collected 
for the determination of plasma concentrations of oxycodone at the predose time point 
(within 15 minutes of dosing); 5, 15, 30, and 60 minutes after dosing; and 2, 4, 6, 8, 12, 
and 24 hours after dosing. For subjects under age 2, serial blood samples for PK analysis 
will be collected prior to the first dose (within 15 minutes of dosing); 15, 30, and 60 
minutes after dosing; and 2, 6, 12, and 24 hours after dosing. 
7.2 
Discussion of Study Design 
This is an open-label, nonrandomized, multicenter study designed to assess the 
pharmacokinetics and safety of the product oxycodone hydrochloride USP oral solution, 
5 mg per 5 mL, in pediatric and adolescent subjects <17 years of age following a surgical 


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procedure and expected to require postoperative opioid analgesia and to require an 
indwelling IV catheter for a minimum of 24 hours after being cleared for oral intake.  
Target enrollment will be 110 subjects, including a minimum of 20 subjects under age 2 
(5 subjects ages 0 to <2 months, 5 subjects ages 2 to <6 months, and 10 subjects ages 6 
months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to <17 
years, to evaluate safety in the population.  Subjects within each age group will be evenly 
distributed by age and gender.  In addition, this sample size will allow for an adequate 
evaluable population according to published population PK studies in children21 and 
unofficial FDA guidance on sample size calculations based on estimates of clearance and 
volume of distribution.27  Recruitment projections are based on a review of recent reports 
of adolescent scoliosis surgery showing that major specialty surgical centers average 
10 to 20 patients per year in this age group.28-32 
7.3 
Study Sites 
The study will take place at up to 10 sites in the US. 
7.4 
Point of Contact 
A point of contact will be identified to provide subjects with information on the study, 
subject rights, and whom to contact in case of study-related injury. This information will 
be provided in the subject information and informed assent and consent forms. 
8. SUBJECT POPULATION 
8.1 
Selection of Study Population 
8.1.1 
Inclusion Criteria 
A subject will be eligible for inclusion in the study if he or she meets the following 
criteria: 
1 
Is male or female <17 years of age at the time of dosing. 
2 
Subject 2 to <17 years of age, be in at least the 25% for weight according to the 
Center for Disease Control pediatric growth charts and weighs at least 28 lb at the 
time of dosing with study drug. 
3 
Is generally healthy as documented by medical history (except for the condition for 
which the procedure is being performed); physical examination (including, but not 
limited to, the cardiovascular, gastrointestinal, respiratory, and central nervous 
systems); vital sign assessments; 12-lead electrocardiograms (ECGs); clinical 
laboratory assessments; and general observations.  Has a negative serum pregnancy 
test at Screening and predose check-in for females of childbearing potential. 
4 
Is an outpatient for a surgical procedure and is expected to remain hospitalized for at 
least 24 hours after dosing with study drug. 


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5 
Is anticipated to have postsurgical pain requiring a parenteral analgesic regimen by 
using a short-acting opioid analgesic and is anticipated to be switched to an oral 
opioid for at least 1 dose (according to institution standard of care). 
6 
Has an indwelling access catheter for blood sampling. 
7 
Agrees to comply with all protocol requirements.  If not old enough, the legally 
responsible parent(s) or legal guardian(s) must agree to comply with all protocol 
requirements. 
8 
Has been informed of the nature of the study, and informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, in accordance with institutional review 
board requirements. 
8.1.2 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets the following criteria: 
1 
Has the presence or history of a clinically significant disorder involving the 
cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, 
endocrine, or neurologic system(s) or psychiatric disease (except for the condition for 
which the procedure is being performed) as determined by the clinical investigator. 
2 
Has any clinical laboratory test result outside the normal range. 
3 
Has a positive test result for hepatitis B surface antigen, hepatitis C antibody, or 
human immunodeficiency virus antibody. 
4 
Has a clinically significant illness, except for the condition for which the procedure is 
being performed, in the 28 days before dosing with study drug as determined by the 
clinical investigator. 
5 
Is a lactating or breastfeeding female. 
6 
Uses any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) 
or 28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing 
with study drug. Use of all other prescription medications, except required pre-op 
medications and birth control, is prohibited within 3 days of dosing with study drug.  
Use of any over-the-counter medications (including herbal or dietary supplements and 
therapeutic doses of vitamins), except for required pre-op medications, is prohibited 
within 24 hours of dosing with study drug, with the exception of topical spermicide.  
Use of St. John’s wort is prohibited from 28 days before dosing until 14 days after 
dosing.  Standard daily dose multivitamins (nontherapeutic doses) may be taken until 
enrollment into the study but will be restricted during the study. 
7 
Consumes alcohol-, caffeine-, or xanthine-containing products within 48 hours before 
dosing and during periods when blood samples are collected. 


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8 
Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-containing 
products within 14 days of dosing.  Fruit juices, with the exception of apple and 
grape, will be prohibited during the study. 
9 
Is a smoker or has used nicotine or nicotine-containing products within 30 days of 
dosing. 
10 Has a history of alcohol or drug addiction or abuse within the last year. 
11 Subject 2 to <17 years of age, has a positive urine test result for drugs of abuse 
(amphetamines, barbiturates, cannabinoids, cocaine metabolites, opiates, 
phencyclidine, and benzodiazepines) or alcohol at Screening (not required for 
subjects less than 2 years of age). 
12 Donated blood within 28 days or plasma within 14 days of dosing or plans to donate 
them within 4 weeks after completing the study. 
13 Has a history of relevant drug allergies, food allergies, or both (i.e., allergy to 
oxycodone, allergy to related drugs, or any significant food allergy that could 
interfere with the study). 
14 Is intolerant to direct venipuncture. 
15 Received an investigational drug within 28 days of dosing. 
16 Has taken oxycodone or oxymorphone within the 48 hours before anticipated dosing 
with study drug. 
17 Is not suitable for entry into the study in the opinion of the investigator. 
8.2 
Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from participation in this study at any time for any 
reason and without prejudice. 
The investigator may terminate a subject from the study at any time for lack of 
therapeutic effect that is intolerable to the subject or otherwise considered unacceptable, 
for intolerable or unacceptable AEs, intercurrent illness, noncompliance with study 
procedures, administrative reasons, or unsuitability for the study in the investigator’s 
opinion to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate case report form (CRF).  Whenever possible and reasonable, 
evaluations that were scheduled for study completion should be performed at the time of 
premature discontinuation. 
Subjects who discontinue from the study will not be replaced. 


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9. STUDY TREATMENTS 
9.1 
Method of Assigning Subjects to Treatment Groups 
9.1.1 
Under Age 2 
Subjects under age 2 who meet all eligibility criteria will receive a single dose of 
Oxycodone Oral Solution.  This will be an open-label study and does not require 
randomization. 
9.1.2 
Ages 2 to <17 
Subjects ages 2 to <17 who meet all eligibility criteria will be scheduled to receive single 
or multiple doses of Oxycodone Oral Solution.  This will be an open-label study and does 
not require randomization. 
9.2 
Identification of Investigational Products 
The study drug is Oxycodone Oral Solution (5 mg/5 mL) manufactured by VistaPharm 
(Largo, FL).  Oxycodone Oral Solution is a red solution intended for oral administration. 
Oxycodone Oral Solution will be supplied in 500-mL bottles.  Oxycodone Oral Solution 
contains 4.5 mg of oxycodone free base per 5 mL (5 mg oxycodone HCl/5 ml) and the 
following inactive ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid 
anhydrous USP, glycerin natural USP, sorbitol solution 70% USP, FD&C Red #40, 
raspberry flavor, and water. 
VistaPharm will provide an adequate supply of study drug to the sites. 
Ketorolac for injection (15 mg/mL or 30 mg/mL), Morphine Sulfate for injection (2 
mg/mL), and Fentanyl via NCA for use as a rescue medication will be provided by the 
study site pharmacy. Should other rescue medication be required they will be provided by 
the study site pharmacy. 
9.3 
Treatment Administered 
The study drug will be administered only to eligible subjects under the supervision of the 
investigator or identified subinvestigator(s). 
9.3.1 
Under Age 2 
Each subject will receive a single dose of Oxycodone Oral Solution in place of the 
standard analgesic dose after being postoperatively cleared to transition to oral pain 
medication.  The dose will be determined based on PK modeling from the interim 
analyses.  Oxycodone Oral Solution will be administered with an oral medication syringe. 
9.3.2 
Ages 2 to <17 
Each subject will receive a dose of Oxycodone Oral Solution (0.1 mg/kg for children 
ages 2 to 6, 0.08 mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to 17) in place of the 
standard analgesic dose after being postoperatively cleared to transition to oral pain 


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medication.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, 
who will be included in the first interim analysis, will only receive 1 dose of Oxycodone 
Oral Solution.  Subjects enrolled in the study after the interim analysis is completed may 
receive additional doses every 4-6 hours as needed.  Oxycodone Oral Solution will be 
administered with an oral medication syringe.   
9.4 
Storage 
Oxycodone Oral Solution will be stored in a locked facility with restricted access.  This 
may be a locked cabinet or room for which the number of keys is limited and in 
compliance with standards of the Drug Enforcement Administration for Schedule II 
narcotics.  Chain of custody of the study drug will be followed in accordance with the 
individual site’s standard procedures, which will be documented by the site and provided 
to the sponsor.  The study drug will be stored at controlled room temperature between 
20°C and 25°C (68°F-77°F).  The sponsor will provide to the site personnel instructions 
for the storage and return of used and unused study drug. 
9.5 
Labeling 
Each container of study drug will be labeled with study-specific information that meets 
all applicable regulatory requirements. 
9.6 
Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, 
or other disposition of study drug, including the date, quantity, batch or code number, and 
identification of subjects (subject number and initials) who received study drug.  The 
investigator will not supply study drug to any person except those named as 
subinvestigators on the FDA 1572, designated staff, and subjects in this study.  The 
investigator will not dispense study drug from any sites other than those listed on the 
FDA 1572.  Study drug may not be relabeled or reassigned for use by other subjects. 
Upon completion of the study, unused supplies of study drug will be reconciled by the 
investigator and returned to the sponsor as directed. 
9.7 
Blinding and Unblinding Treatment Assignment 
Not applicable. 
9.8 
Selection of Dose in the Study 
The published literature on treatment of pediatric pain with oxycodone reports doses 
ranging from 0.125 to 0.2 mg/kg, up to a maximum of 15 mg, for treatment of acute 
musculoskeletal pain, including suspected fractures in emergency room settings, for 
treatment of undifferentiated abdominal pain, and for pediatric burn wound care in 
outpatient clinics.33-36  A PK modeling has been conducted using the data derived from 
the 4 studies conducted in the adult population. Based on these population data, the test 
dose chosen for subjects ages 2 to 6 is 0.1 mg/kg, ages 7 to 12 is 0.08 mg/kg, ages 13 to 
17 is 0.07 mg/kg, and a dose to be determined based on PK modeling from the interim 
analyses for subjects under age 2, given when the subjects have been cleared for oral 


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intake and in place of the analgesic regimen (nonoxycodone and nonoxymorphone) 
prescribed postoperatively for subjects by their attending physicians according to 
institutional SOCs.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age 
groups, who will be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the study after the 
interim analysis is completed may receive additional doses every 4-6 hours as needed.   
The dose for subjects under age 2 will be determined based on PK modeling from the 
interim analyses. 
9.9 
Selection of Timing of Dose for Each Subject 
The design of the study and the timing of dosing were selected to provide the appropriate 
basis for assessing the PK parameters of oxycodone following administration of the first 
dose. 
9.10 Treatment Compliance 
All study drugs will be administered in the hospital by study personnel and recorded in 
the CRF.  Study personnel will confirm that the subject ingests the entire dose of study 
drug. 
The date and time of study drug administration will be recorded on the appropriate page 
of the CRF.  If a subject does not receive the study drug, the reason for the missed dose 
will be recorded. 
9.11 Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate CRF. The 
medication name, dose, including frequency, date, and indication for use must be 
recorded.  Time of rescue medication will also be recorded. The medical monitor should 
be notified in advance of (or as soon as possible after) any instances in which prohibited 
therapies or rescue medications are administered.  Medications and therapies that are 
considered necessary for the subject’s welfare and will not interfere with the response to 
the study medication may be given at the discretion of the investigator. 
9.11.1 
Permitted Therapies 
Concomitant medications (with the exceptions described in Section 9.11.2) are allowed, 
but should be limited to only those medications considered necessary. 
Nausea and vomiting are common opioid-induced AEs for which subjects do develop a 
tolerance. Subjects who undergo surgery requiring opioid analgesia for an extended 
period of time may develop these AEs.  Therefore, it is expected that some subjects will 
need to be given an antiemetic. Any antiemetic used during treatment with study drug 
should be recorded as a concomitant medication. 


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9.11.2 
Prohibited Therapies 
Use of any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) or 
28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing with 
study drug through the end of the study is prohibited. Use of all other prescription 
medications, with the exception of allowable pre-op medications and birth control, is 
prohibited within 3 days of dosing with study drug.  Use of any monoamine oxidase 
inhibitor is prohibited until 14 days after the final dose of study drug. 
Use of any over-the-counter medications (including herbal or dietary supplements and 
therapeutic doses of vitamins), except for allowable pre-op medications, is prohibited 
within 24 hours of dosing with study drug, with the exception of topical spermicide.  Use 
of St. John’s wort is prohibited from 28 days before dosing until 14 days after dosing.  
Standard daily dose multivitamins (nontherapeutic doses) may be taken until enrollment 
into the study but will be restricted during the study.   
Restrictions: 
Females of childbearing potential must be practicing abstinence or using a medically 
acceptable form of contraception (e.g., intrauterine device, hormonal birth control, or 
double-barrier method).  For the purpose of this study, all females who are menstruating 
will be considered to be of childbearing potential unless they are biologically sterile or 
surgically sterile for more than 1 year. 
Consumption of alcohol-, caffeine-, or xanthine-containing products within 48 hours 
before dosing and during periods when blood samples are collected is prohibited.  
Consumption of grapefruit, grapefruit products, Seville oranges, or pomelo-containing 
products is prohibited within 14 days of dosing with study drug.  All types of fruit juices, 
with the exception of apple and grape, and fruit-containing popsicles will be prohibited 
during the study. 
Subjects who smoke or use nicotine or nicotine-containing products within 30 days of 
Screening will be excluded from study participation. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for 
continuation in the study at the discretion of the sponsor, investigator, medical monitor, 
or other authority. 
9.12 Rescue Medication 
In subjects ages 2 to <17 years, if pain control is inadequate with Oxycodone Oral 
Solution, the investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 
6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue 
medication for breakthrough pain after dosing. Use of other rescue pain medication is 
permissible in accordance with hospital pain management guidelines or facilities standard 
of care.  Any rescue medications used will be provided by the study site pharmacy. 


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In subjects under age 2, if pain control is inadequate with Oxycodone Oral Solution, as 
indicated by a score of moderate to severe (4-10) on the FLACC, the subject will be 
given Fentanyl via NCA.  The Fentanyl will be provided by the study site pharmacy. 
10. STUDY PROCEDURES 
Subjects’ legally responsible parent(s) or legal guardian(s) will provide written informed 
consent and subjects will provide written informed assent (as appropriate) before any 
study-related procedures are initiated, including the cessation of prohibited concomitant 
therapy. 
Table 2 (Section 17) presents the schedule of events to be performed during the study. 
10.1 Screening (Day −14 to Day −1) 
Subjects must be screened within 14 days before enrollment in the study.  The following 
procedures will be performed at Screening: 
• Obtain written informed consent and assent (as appropriate). 
• Review inclusion and exclusion criteria. 
• Collect demographic information. 
• Record medical history, including prior and current therapies (e.g. prescription 
and nonprescription medications). 
• Perform a physical examination including weight, height, body mass index, and 
vital signs (blood pressure, heart rate, respiratory rate, and oral temperature).   
• Perform serum pregnancy test for all females of childbearing potential. 
• Perform urine drug screen (Section 11.2.2), excluding subjects < 2 years of age. 
• Perform 12-lead ECG. 
• Collect blood and urine samples for clinical laboratory tests (complete blood 
count with differential, clinical chemistry, serology, and urinalysis) (Section 
11.2.2). 
10.2 Predose Check-in (Day −1) 
The predose check-in (Day −1) can be performed the same day as surgery (Day 1) at 
which time eligibility and prior medications will be reviewed and updated as needed.  
Medical history will be recorded, if it was not completed at Screening, and vital signs 
will be obtained.  Following surgery, subjects will receive standard care, including 
parenteral analgesia with a nonoxycodone, nonoxymorphone medication that will not 
interfere with the measurement or metabolism of oxycodone. 
10.3 Open-Label Treatment (Day 1, After Surgery) 
The following procedures will be performed on Day 1: 
• Measure blood pressure, heart rate, and respiratory rate before dosing (within 
90 minutes) with Oxycodone Oral Solution and every 15 minutes for 4 hours after 


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dosing, then every 2 hours until 24 hours after the first dose of Oxycodone Oral 
Solution. 
• Measure temperature every 2 hours for 24 hours after the first dose of Oxycodone 
Oral Solution. 
• Continuous pulse oximetry beginning as soon as possible following procedure 
through 8 hours after the last study dose of Oxycodone Oral Solution.  The following 
timepoints will be captured in the CRF: 5, 10, 30 and 60 minutes, 2 hours, then every 
2 hours until 8 hours after the last study dose of Oxycodone Oral Solution. 
• Assess pain in subjects under 2 years of age by using the FLACC prior to and 20, 40, 
60, 90, 120, 180, and 240 minutes after the first dose of Oxycodone Oral Solution.  
The FLACC will also be administered prior to the subject receiving each dose of 
Fentanyl. 
• Record concomitant medication use. 
• Assess and record AEs prior to dosing and throughout the remainder of Day 1. 
• For subjects 2 to <17 years of age, collect serial blood samples for PK analysis at the 
predose time point (within 15 minutes of dosing); 5, 15, 30, and 60 minutes after 
dosing; and 2, 4, 6, 8, 12, and 24 hours after the first dose of Oxycodone Oral 
Solution. For subjects under age 2, serial blood samples for PK analysis will be 
collected prior to the Oxycodone Oral Solution dose (within 15 minutes of dosing); 
15, 30, and 60 minutes after dosing; and 2, 6, 12, and 24 hours after dosing. 
• After subjects ages 2 to <17 have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of 
Day 1 in place of the standard analgesic medication.  The first 10 subjects in each of 
the 2 to 6, 7 to 12 and 13 to <17 age groups, who will be included in the first interim 
analysis, will only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age 
groups enrolled in the study after the interim analysis is completed may receive 
additional doses every 4-6 hours as needed.  If pain control is inadequate with 
Oxycodone Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 
hours as rescue medication for breakthrough pain after dosing.  Use of other rescue 
pain medication is permissible in accordance with hospital pain management 
guidelines or facilities standard of care. 
• After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero 
of Day 1 in place of the standard analgesic medication.  The dose will be determined 
based on PK modeling from the interim analyses.  If pain control is inadequate with 
Oxycodone Oral Solution, as indicated by a score of moderate to severe (4-10) on the 
FLACC, the subject will be given Fentanyl via NCA. 
Water, Gatorade, Powerade, and Popsicles will be allowed for the first hour (1 hour) 
following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study. 


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10.4 End-of-Study/Early Discontinuation 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 
24 hours after dosing with Oxycodone Oral Solution. 
The following procedures will be performed at the End-of-Study/ Early Discontinuation 
visit: 
• Measure vital signs (blood pressure, heart rate, and respiratory rate). 
• Clinical laboratory testing (complete blood count with differential and clinical 
chemistry). 
• Record concomitant medications. 
• Record AEs. 
After these procedures are performed, the study staff will determine whether it is safe for 
the subject to be discharged from the study. 


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11. STUDY ASSESSMENTS 
11.1 Pharmacokinetics 
Blood samples for PK assessments in the subjects 2 to <17 years of age will be collected 
at the predose time point (within 15 minutes of the first dose of Oxycodone Oral 
Solution); 5, 15, 30, and 60 minutes after dosing; and 2, 4, 6, 8, 12, and 24 hours after the 
first dose of Oxycodone Oral Solution.  For subjects under age 2, blood samples for PK 
analysis will be collected prior to the Oxycodone Oral Solution dose (within 15 minutes 
of dosing); 15, 30, and 60 minutes after dosing; and 2, 6, 12, and 24 hours after dosing. 
Time Zero is the time of the first dose of Oxycodone Oral Solution. 
The following PK parameters will be calculated: 
• Area under the plasma concentration versus time curve from Time Zero to the last 
measurable concentration (AUC0-t) 
• Area under the plasma concentration versus time curve from Time Zero to infinity 
(AUC0-inf) 
• Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• Maximum measured plasma concentration (Cmax) 
• Time of the maximum measured plasma concentration (Tmax) 
• Apparent first-order terminal elimination rate constant (Kel) 
• Apparent first-order terminal elimination half-life (t1/2) 
• Apparent clearance (CL/F) 
• Volume of Distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
11.1.1 
Sample Collection 
Blood collection will be performed using an existing indwelling access catheter (arterial 
or venous noted on CRF) at the start of the study (the use of Emla at the insertion site is 
permitted).  All catheter lines should be appropriately flushed per institutional SOC 
before each blood draw.  The 0.5-mL blood samples will be obtained and placed into 
2.0-mL K3 ethylenediamine tetra-acetic acid tubes at each blood collection time point.  
The labels for all biological sample collection and storage containers will contain, at a 
minimum, the subject's number, protocol number, collection date, and scheduled 
collection time (study hour). 


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Study Visit/Phase 
Amount Collected 
(mL) 
Number of 
Samples 
Collected 
Total Amount 
Collected per 
Subject (mL) 
Screening Serum Chemistry and Hematologya 
2.5 mL 
1 
2.5 mL 
Pharmacokinetics (2 to <17 years old) or 
0.5 mL 
11 
5.5 mL 
    Pharmacokinetics (<2 years old) 
0.5 mL 
8 
4.0 mL 
End of Study Serum Chemistry and 
Hematology 
2.5 mL 
1 
2.5 mL 
Grand Total 
-- 
-- 
14.0 – 20.5 mLb 
a Where possible, results from clinical laboratory tests performed as part of the standard of care (SOC) will be used for study 
purposes.  A separate blood draw for the clinical laboratory test portion of this protocol will occur only if the clinical laboratory 
tests as part of the SOC will not be available to coincide with the approximate time scheduled by the protocol.  Preoperative or 
intraoperative (collected before the incision) test results must be available for review by the investigator before enrolling any 
subject into the study.  Procedures for blood draws should follow institutional SOC. 
b The total includes up to 10-mL discard volume for all 11 pharmacokinetic and laboratory testing samples, for the 2 to <17 year 
olds.  Total blood volume drawn for research purposes must not exceed 3% of subject’s total blood volume, which is assumed to be 
75 mL/kg.  
11.1.2 
Blood Volumes 
Existing blood draw guidelines for pediatric research suggest minimal risk is between 3% 
and 5% of total blood volume (TBV) over 24 hours or on a single draw, and TBV is 
generally estimated at 75-80 mL/kg.  For the smallest child permitted per protocol from 
ages 2 to <17 years (weight: 28 lbs or 12.7 kg), the TBV would be estimated at 952.5 ml. 
The maximum safe volume drawn would therefore be between 28 and 47 mL, based on 
minimal risk at 3-5% TBV over 24 hours.  The required 10.5 mL plus up to 10 mL of 
discard volume, or a cumulative volume of 20.5 mL, is well under the 3-5% of TBV 
guideline for the smallest eligible participant using the smallest estimation of TBV.26 For 
the child less than 2 years of age, there is a maximum of 8 serial blood samples of 0.5 mL 
each for a total of 4.0 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 9 mL is under the 3-5% of 
TBV guideline. 
11.1.3 
Sample Processing 
Immediately after collection, the tube will be gently inverted several times to mix the 
anticoagulant with the blood sample.  The plasma fraction will be separated by placing 
the collection tube into a refrigerated centrifuge (4°C to 8°C) for 10 minutes at 
approximately 1500g or 3000 RPM.  The plasma fraction will be withdrawn by pipette 
and placed into polypropylene freezing tubes in 2 approximately equal aliquots.  All 
sample collection and freezing tubes will be clearly labeled in a manner that identifies the 
subject and the collection time.  Labels will be fixed to the freezing tubes in a manner 
that will prevent the label from becoming detached after freezing.  All plasma samples 
will be placed into a freezer at approximately −20°C (± 10°C) or below until transfer or 
shipment to the bioanalytical laboratory. The time between sample collection and freezer 
storage should not exceed 90 minutes.  The additional blood draws for the purposes of 
pharmacokinetic assessment in this study do not pose more than a minor risk to the 
subjects. 


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11.1.4 
Transport of Samples 
The clinic staff will inventory the samples that are to be shipped to the bioanalytical 
laboratory.  Each shipment will contain a complete set of samples.  The second set of 
samples will not be shipped until receipt of the first shipment is confirmed.  The 
inventory record will accompany the frozen plasma samples as per standard operating 
procedures. 
For sample shipment requiring a third party courier, the samples will be packed in ample 
dry ice within a styrofoam container to ensure the samples will remain frozen for at least 
72 hours and will be shipped via express delivery to the bioanalytical facility.  Written 
notification of sample shipment will be communicated to the bioanalytical facility and the 
sponsor.  The samples will be tracked to assure arrival in a safe and timely manner. 
The shipment will be accompanied by logs showing the name of the study drug, protocol 
number, and the subject numbers and samples included in the shipment.  Documentation 
noting what the condition of the samples upon arrival at the bioanalytical laboratory is 
and whether the amount of dry ice remaining is adequate or inadequate should be 
returned to the clinic. 
The samples will be shipped frozen to: 
PPD - Houston 
10550 Rockley Road, Suite 150 
Houston, TX 77099, USA 
11.1.5 
Analytical Procedures 
11.1.5.1 Bioanalytical Sample Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be measured using a validated liquid chromatography–mass 
spectrometry assay method.  The validated detection range for oxycodone is 0.2 to 
125 ng/mL in human plasma. 
Samples from subjects who withdraw consent/assent or are dropped from the study will 
not be analyzed unless otherwise requested by the sponsor. 
Samples from subjects who have been dropped from the study because of emesis 
according to PPD’s standard operating procedures will not be analyzed. 
11.1.5.2 Bioanalytical Methodology 
The bioanalytical method, assay validation, and bioanalytical report for this study will be 
provided by the bioanalytical investigator.  Full validation of a sensitive assay for the 
appropriate analytes in biological fluid, including precision, accuracy, reproducibility, 
and selectivity will be included in the final report.  The bioanalytical report will include 
the stability of the frozen samples, limit of quantitation, recovery, and a summary of the 
standard curves. 


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11.2 Safety 
Safety will be assessed during the study by the monitoring and recording of AEs, clinical 
laboratory test results (hematology, biochemistry, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, and respiratory rate), 
temperature, pulse oximetry, and physical examination findings. 
11.2.1 
Adverse Events 
11.2.1.1 Adverse Event Definitions 
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation patient administered a pharmaceutical product that does not necessarily 
have a causal relationship with the product.  An AE can therefore be any unfavorable and 
unintended sign (including a new, clinically important abnormal laboratory finding), 
symptom, or disease temporally associated with the product, whether or not it is related to 
the product. 
Preexisting diseases or conditions will not be considered AEs unless there is an increase 
in the frequency or severity, or a change in the quality, of the disease or condition.  
Worsening of a preexisting condition is considered an AE. 
An expected AE is one for which the nature or severity is consistent with the known AE 
profile of the product.  For an investigational drug, the known information is contained in 
the investigator brochure.  For a marketed drug, the known information is in the current 
package insert. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current investigator brochure or package insert.  For example, hepatic necrosis would be 
unexpected (greater severity) if the investigator brochure or package insert only listed 
elevated hepatic enzymes or hepatitis.  Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the investigator brochure or 
package insert only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a 
known, already documented adverse reaction constitute unexpected AEs.  Examples 
include acute renal failure as an expected adverse reaction with a subsequent new 
occurrence of interstitial nephritis and hepatitis with a first occurrence of fulminate 
hepatitis. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly 
• Is an important medical event 


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Medical and scientific judgment should be used in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent another of the outcomes listed in the 
definition previously.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study 
drug or a hospital admission for a diagnostic evaluation of an AE does not qualify the 
condition or event as an SAE.  A newly diagnosed pregnancy in a subject who has 
received a study drug is not considered an SAE unless it is suspected that the study drug 
interacted with a contraceptive method and led to the pregnancy; however, the medical 
monitor should be made aware of a newly diagnosed pregnancy as soon as possible after 
site notification.  A congenital anomaly in an infant born to a mother who was exposed to 
the study drug during pregnancy is an SAE. 
11.2.1.2 Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 11.2.1.1) are recorded in the CRF and reported to the medical monitor 
(Section 11.2.1.3).  Adverse events will be collected from the time of the first dose of 
Oxycodone Oral Solution through the End of Study or Early Discontinuation visit. 
At each visit, subjects will be asked a standard question to elicit any medically related 
changes in their well-being.  They will also be asked if they have had any accidents, used 
any new medications, or changed concomitant medication regimens (both prescription 
and over-the-counter medications).  In addition to subject observations, AEs will be 
documented from any data collected on the AE page of the CRF (e.g., clinical laboratory 
values, physical examination findings, and ECG changes) or other documents that are 
relevant to subject safety. 
11.2.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the 
CRF.  Information to be collected includes drug treatment, type of event, time of onset, 
dose, investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome.  Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, reactions to concurrent medications, or progression of disease states must also 
be reported.  All AEs will be followed to adequate resolution.  The latest version of the 
Medical Dictionary of Regulatory Activities will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 


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The investigator or designee must report any AE that meets the criteria for an SAE 
(Section 11.2.1.1) to the medical monitor within 24 hours of first becoming aware of the 
event by telephone.  At the time of first notification, the investigator or designee should 
provide at a minimum the following information if available: 
• Protocol number 
• Subject’s study identification and initials 
• Subject’s date of birth 
• Date of dose of study drug 
• Time and date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
Within 24 hours of the initial telephone notification, the investigator must fax a written 
SAE report form to the medical monitor.  Any missing or additional relevant information 
about the SAE should be provided in a written follow-up SAE report form.  The 
investigator should also ensure that any additional information requested about the event 
(e.g., hospital reports, autopsy reports) is provided as soon as it is available. 
The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of the institutional review board (IRB). 
The following contact information is to be used for SAE reporting: 
 
Thomas J. Hochadel, Pharm.D. 
Cognitive Research Corporation 
200 Central Ave, Suite 1230 
Saint Petersburg, FL 33701 
Telephone: 727-897-9000 
Cell: 727-515-1334 
Fax: 727-897-9000 
11.2.1.3.1 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which it affects the subject’s 
daily activities.  Severity will be rated as mild, moderate, or severe using the following 
criteria: 
Mild: 
Is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere 
with usual activities of daily living. 
Moderate: 
Is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent 
risk of harm to the subject. 
Severe: 
Interrupts usual activities of daily living, significantly affects 


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clinical status, or may require intensive therapeutic intervention 
Changes in the severity of an AE should be documented to allow assessment of the 
duration of the event at each level of intensity to be performed.  Adverse events 
characterized as intermittent require documentation of onset and duration of each 
episode. 
11.2.1.3.2 Assessment of Relationship 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will 
be characterized using the following classification and criteria: 
Not related: 
An AE with sufficient evidence to accept that there is no causal 
relationship to administration of study drug (e.g., no temporal 
relationship because the study drug was administered after the 
onset of the event, an investigation shows that study drug was 
not administered, another cause was proven.) 
Unlikely related: 
An AE, including a clinical laboratory test abnormality, with a 
temporal relationship to administration of study drug that makes 
a causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
Possibly related: 
An AE with a reasonable time sequence to administration of 
study drug but that could also be explained by concurrent 
disease or other drugs or events.  Information on drug 
withdrawal may be lacking or unclear. 
Related: 
An AE occurring in a plausible time relationship to 
administration of study drug and that cannot be explained by a 
concurrent disease or other drugs or events.  The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 
11.2.1.3.3 Definition of Adverse Event Start Date, Stop Date, and Duration  
Start date: 
The date at which the AE is first noted 
Stop date: 
The date at which the AE is known to be resolved.  If it has not known 
to have stopped, then indicate “ongoing.” 
Duration: 
A time in days, hours, or minutes 


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11.2.1.3.4 Action(s) Taken 
Action(s) taken may consist of the following (as appropriate): 
None: 
No actions taken. 
Discontinued study 
drug: 
Study drug was permanently discontinued because of the AE. 
Treatment:  
Specified medication (to be listed on the concomitant medication 
chart) was used as a countermeasure. 
Others: 
Other actions, such as an operative procedure, were required 
because of the AE. 
11.2.1.3.5 Definition of Adverse Event Outcome at the Time of Last Observation 
The AE outcome at the time of last observation will be classified as “resolved,” “resolved 
with sequelae,” “ongoing,” “death,” “other,” or “unknown.” 
“Death” should only be selected as an outcome when the AE resulted in death.  If more 
than 1 AE is possibly related to the subject’s death, the outcome of death should be 
indicated for each such AE.  Although “death” is usually an event outcome, events such 
as sudden death or unexplained death should be reported as SAEs. 
11.2.1.4 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after dosing with study drug) to a 
satisfactory resolution or until the investigator deems the event to be chronic or not 
clinically significant or the subject to be stable.  All findings relevant to the final outcome 
of an AE must be reported in the subject’s medical record and recorded on the 
appropriate CRF. 


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11.2.2 
Laboratory Safety Assessments 
Samples for the following laboratory tests will be collected at the time points specified in 
the Schedule of Events (Section 17). 
Hematology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic transaminase), 
glucose (fasting), albumin, and total protein 
Serology:  
Includes human immunodeficiency virus test, hepatitis B 
surface antigen test, and hepatitis C virus 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, 
microscopic urine analysis if dipstick positive 
Serum pregnancy 
test: 
Conducted for women of childbearing potential only 
Urine drug screen 
Includes amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, ethyl alcohol, and 
benzodiazepines 
Each safety laboratory assessment blood sample will be 2.5 mL in volume. The total 
amount of blood to be drawn will be a maximum of 19.5 mL per subject, including 11 
samples for PK assessments (0.5 mL each). 
11.2.3 
Vital Signs 
Vital signs, including heart rate, respiratory rate, and blood pressure will be measured at 
the time points specified in the schedule of events (Section 17) after the subject has been 
in a sitting position for 5 minutes.  Oral body temperature will also be measured. 
11.2.4 
Pulse Oximetry 
Continuous pulse oximetry will begin as soon as possible following the procedure and 
will continue until 8 hours after the last study dose of Oxycodone Oral Solution.  The 
following timepoints will be captured in the CRF: 5, 10, 30 and 60 minutes, 2 hours, then 
every 2 hours until 8 hours after the last study dose of Oxycodone Oral Solution. 
11.2.5 
Electrocardiogram 
An ECG will be performed at Screening only. 
11.2.6 
Physical Examination 
A standard physical examination will be performed at Screening.  The examination will 
include assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, 


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cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities.  Interim 
physical examinations will be performed at the investigator’s discretion if necessary to 
evaluate AEs or clinical laboratory abnormalities. 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) (See Attachment 17.4) 
will be used to measure pain in subjects under age 2 prior to and 20, 40, 60, 90, 120, 180, 
and 240 minutes after the dose of Oxycodone Oral Solution.  The FLACC will also be 
administered prior to the subject receiving each dose of Fentanyl. 
The FLACC provides a simple framework for quantifying pain behaviors in children who 
are unable to verbalize the presence or severity of pain.37 
Additionally, time of rescue medication will also be evaluated. 
12. STATISTICAL METHODS 
12.1 General Considerations 
Descriptive statistics will be provided for all demographic, safety, and PK parameters.  
No formal statistical testing will be performed for this study. 
A statistical analysis plan (SAP) that describes the details of the analyses to be conducted 
will be written before database lock. 
12.2 Analysis Populations 
The following analysis populations are planned for this study: 
• PK Population: the PK population will consist of all subjects who receive the 
study drug and have at least 1 measureable plasma concentration. 
• Safety Population: the safety population will consist of all subjects who receive 
the study drug. 
12.3 Statistical Analyses 
12.3.1 
Subject Disposition and Demographic Characteristics 
For categorical variables, frequencies and percentages will be presented.  Continuous 
variables will be summarized by using descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized.  The number of 
subjects who enroll in the study and the number and percentage of subjects who complete 
the study will be presented.  The frequency and percentage of subjects who withdraw or 
discontinue from the study, along with the reason for withdrawal or discontinuation, will 
also be summarized. 


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12.3.2 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be listed and summarized.  Each subject’s oxycodone plasma 
concentrations will be graphed using both a normal scale y-axis and a logarithmic scale 
y-axis.  Mean oxycodone plasma concentrations will also be graphed using scheduled 
elapsed sampling times for both the normal and logarithmic scale y-axis. 
Pharmacokinetic parameters will be listed for each subject and summarized.  Key PK 
parameters will be contrasted with adult values from the previously conducted PK 
studies. 
Other PK analyses may be performed as appropriate. 
12.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and will be summarized 
overall.  Adverse events will also be summarized by severity and relationship to study 
drug.  Serious AEs and AEs leading to discontinuation of study drug will also be 
summarized. 
Actual values and changes from Baseline for clinical laboratory results, vital sign 
measurements, temperature, and pulse oximetry will be summarized at each time point 
using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) or shift tables where appropriate.  Physical examination findings will be 
presented in a listing. 
12.3.4 
Exploratory Analyses 
The change from baseline in total FLACC Score will be summarized at each time point.  
The total amount of Fentanyl will also be evaluated. 
12.3.5 
Interim Analyses 
 An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects ages 6 
months to <2 years will receive will be based on this interim analysis. 
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on PK modeling from the interim analysis. 


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12.4 Sample Size Determination 
The evaluable sample size for this study is powered to target a 95% confidence interval 
within 60% and 140% of the geometric mean estimates of clearance and volume of 
distribution for oxycodone with at least 80% power. 
Estimates of the coefficient of variation for the clearance and volume of distribution of 
oxycodone were 25.72% and 71.12%, respectively, and were based on estimated standard 
deviations of (log-transformed) clearance and volume as provided in a June 28, 2012 PK 
modeling technical report.  The above mentioned values for % coefficient of variation 
(%CV) are derived using the approximation: 
 
, 
 
where SD are the standard deviations given in the technical report, with values of 0.2531 
and 0.6398 for clearance and volume, respectively.  The methodology for samples size 
calculation is as given in Wang, et al.27   
Because of an anticipated dropout rate of 33%, a recruited sample size of 30 subjects is 
considered sufficient to ensure 20 evaluable subjects to assess the PK profiles of 
Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, the trial will 
enroll 110 subjects to gather adequate safety information. 
13. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the 
investigator and associated personnel prior to the study, periodic monitoring visits, and 
meticulous data management. 
13.1 Sponsor and Investigator Responsibilities 
13.1.1 
Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15).  The sponsor reserves the right to withdraw a subject from the study 
(Section 8.2), to terminate participation of a study site at any time (Section 13.7), or to 
discontinue the study (Section 13.6.2). 
The sponsor agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
13.1.2 
Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.3), the investigator indicates that he 
or she has carefully read the protocol, fully understands the requirements, and agrees to 


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conduct the study in accordance with the procedures and requirements described in this 
protocol. 
The investigator also agrees to conduct this study in accordance with all laws, 
regulations, and guidelines of the pertinent regulatory authorities, including and in 
accordance with the April 1996 ICH Guidance for Industry E6 Good Clinical Practice 
(GCP) and in agreement with the 1996 Version of the Declaration of Helsinki.  While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing 
the study and for ensuring compliance with the protocol and all applicable regulations 
and guidelines.  The investigator is responsible for maintaining a list of all persons that 
have been delegated study-related responsibilities (e.g., sub-investigators and study 
coordinators) and his or her specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, 
and their specific duties within the context of the study.  Investigators are responsible for 
providing the sponsor with documentation of the qualifications, GCP training, and 
research experience for themselves and their staff as required by the sponsor and the 
relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent 
person.  The investigator agrees, by written consent to this protocol, to cooperate fully 
with compliance checks by allowing access to all study documentation by authorized 
individuals. 
13.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving 
notification from the sponsor or its designee that the study can be initiated at the study 
site.  The study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed assent and consent. 
2. All GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 


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13.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study.  
Subjects may only be rescreened once 30 days or more after the original Screening visit.  
If a subject is eligible to enter the study after having previously failed screening, he or 
she will be assigned a new subject identification number. 
13.4 Study Documents 
All documentation and material provided by the sponsor for this study are to be retained 
in a secure location and treated as confidential material. 
13.4.1 
Good Clinical Practice Documents 
The GCP documents are listed below. 
• Signed original protocol; (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and sub-investigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• FDA Form 1572 
• Any other relevant GCP documents 
The GCP documents must be received from the investigator and reviewed and approved 
by the sponsor or designee before the study site can initiate the study and before the 
sponsor will authorize shipment of study drug to the study site.  Copies of the 
investigator’s GCP documents must be retained at the study site in a secure location.  
Additional documents, including a copy of the protocol and applicable amendment(s), the 
study drug, CRF completion guidelines, copies of regulatory references, copies of IRB 
correspondence, and study drug accountability records should also be retained as part of 
the investigator’s GCP documents.  It is the investigator’s responsibility to ensure that 
copies of all required GCP documents are organized, current, and available for 
inspection. 
13.4.2 
Case Report Forms 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to 
maintain accurate CRFs and source documentation as part of the case histories for all 
subjects whose legally responsible parent(s) or legal guardian(s) sign an informed 
consent form and subjects who sign assent (as appropriate). 
Case report forms are considered confidential documents and should be handled and 
stored accordingly.  The sponsor or its designee will provide the necessary training on the 
use of the specific CRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 


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To ensure data accuracy, CRF data for individual subject visits should be completed as 
soon as possible after the visit.  All requested information must be entered in the 
electronic data capture (EDC) system, if applicable, according to the completion 
guidelines provided by the sponsor or its designee. 
The CRFs may be signed by the investigator or a subinvestigator.  These signatures serve 
to attest that the information contained in the CRF is accurate and true. 
13.4.3 
Source Documents 
All information recorded in the EDC system must be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory notes, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files.  
Before the study starts, a list identifying any data to be recorded directly on the CRFs 
(i.e., no prior written or electronic record of data) and considered to be source data will 
be provided. 
Clinical laboratory data required by the protocol will be electronically transferred from 
the central laboratory to the sponsor or its designee. A paper copy of the laboratory 
results will be provided to the study site and should be retained with each subject’s 
source data. 
13.5 Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical study. 
13.5.1 
Monitoring Procedures 
The sponsor or designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines.  The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site 
at periodic intervals and maintain periodic communication.  The investigator agrees to 
allow the CRA(s) and other authorized sponsor personnel access.  The CRA(s) will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. While on site, the CRA(s) will review: 
• Regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• Consenting procedures 
• AE procedures 
• Storage and accountability of study drug and study materials 


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The CRA will ask for clarification or correction of any noted inconsistencies.  Procedures 
for correcting CRFs are described in the study manual.  As representatives of the sponsor, 
CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to meet 
with the CRA(s) during study site visits; to ensure that study staff is available to the 
CRA(s) as needed; to provide the CRA(s) access to all study documentation, to the 
clinical supplies dispensing and storage area; and to assist the monitors in their activities, 
if requested.  Further, the investigator agrees to allow the sponsor or designee auditors or 
inspectors from regulatory agencies to review records and to assist the inspectors in their 
duties, if requested. 
13.5.2 
Data Management 
The sponsor or designee will be responsible for activities associated with the data 
management of this study.  The standard procedures for handling and processing records 
will be followed per GCP and the sponsor’s or CRO’s standard operating procedures.  A 
comprehensive data management plan will be developed including a data management 
overview, database contents, annotated CRF, pre-entry review list, self-evident correction 
conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to 
data queries are described in the study manual. 
13.5.3 
Quality Assurance/Audit 
This study will be subject to audit by the sponsor or designee.  The audits will be 
undertaken to check compliance with GCP guidelines and will include a minimum of: 
• In-house study file audit 
• Audit of computer database quality control 
• Audit of clinical report quality control 
The sponsor or designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used 
for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities 
according to GCP guidelines.  The investigator agrees to cooperate with the auditor 
during the visit and will be available to supply the auditor with CRFs or other files 
necessary to conduct that audit.  Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, 
the investigator shall notify the sponsor immediately. 


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13.6 Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. 
13.6.1 
Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject 
out or last subject last visit) participating in the study.  Within 90 days of the end of the 
clinical study, the sponsor or designee will notify the IRB and regulatory authorities 
about the regular termination of the study as required. 
13.6.2 
Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by the sponsor, 
IRB, regulatory authorities, or the coordinating investigator.  A decision to prematurely 
terminate the study is binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, the sponsor or designee will 
notify the IRB and regulatory authorities as required. The sponsor or designee must 
clearly explain the reasons for premature termination. 
If the study is terminated prematurely, all investigators must inform their subjects and 
take care of appropriate follow-up and further treatment of subjects to ensure protection 
of the subjects’ interests.  Study sites may be asked to have all subjects currently 
participating in the study complete all of the assessments for the Early Termination visit. 
13.7 Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor may terminate 
participation of a study site at any time.  Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol, applicable regulations and guidelines, or both 
• Inadequate subject enrollment 
13.7.1 
Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until at 
least 2 years after the notification of submission of the final study report to regulatory 
authorities by the sponsor. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
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After completing the study, the sponsor will be provided with the original CRFs or at 
least a legible copy and retain the documents at least 5 years after the completion of the 
study. 
One copy will remain with the investigator.  The investigator shall arrange for the 
retention of the subject identification codes, subject files, and other source data until at 
least 5 years after notification of submission of the final study report to the regulatory 
authorities by the sponsor.  These documents need to be retained for a longer period of 
time if required by applicable regulatory authorities or by agreement with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) 
shall be kept by the investigator for the maximum period of time permitted by the 
hospital, institution, or private practice. 
13.7.2 
Sample Retention 
Samples may be used for purposes related to this research.  The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision 
has been made that none of the samples needs to be reanalyzed.  In addition, identifiable 
samples can be destroyed at any time at the request of the subject. 
13.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, 
which requires the written approval by the sponsor.  The protocol amendment must be 
signed by the investigator and approved by the IRB before it may be implemented.  
Protocol amendments will be filed with the appropriate regulatory agency. 
13.9 Use of Information and Publication 
All information about the study drug, the sponsor’s operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by the sponsor or designee to the investigator and not previously published, is 
considered confidential and remains the sole property of the sponsor.  Case report forms 
also remain the property of the sponsor.  The investigator agrees to use this information 
for purposes of study execution through finalization and will not use it for other purposes 
without the written consent of the sponsor. 
The information developed in this study will be used by the sponsor in connection with 
the continued development of the study drug and thus may be disclosed as required to 
other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of the sponsor.  Publication or 
other public presentation of study drug data resulting from this study requires prior 
review and written approval of the sponsor.  Abstracts, manuscripts, and presentation 


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materials should be provided to the sponsor for review and approval at least 30 days prior 
to the relevant submission deadline.  Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, 
poster exhibition, or publication by the investigator until the sponsor has reviewed, 
commented on, and authorized such a presentation or manuscript for publication. 
14. FINAL CLINICAL STUDY REPORT 
The sponsor will retain ownership of the data from this study. 
The final CSR will be written within 1 year of completion of the clinical part of the study.  
This report will include a summary of the study results based on a statistical evaluation 
and clinical assessment of the protocol-defined endpoints. 
The final CSR will be submitted to the regulatory authorities. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents) and the 
1996 Version of the Declaration of Helsinki. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the 
investigator’s informed assent and consent documents, and related subject information 
and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, before any activity or procedure is undertaken 
that is not part of routine care. 
15.3 Approval by Institutional Review Board 
A valid IRB must review and approve this protocol before study initiation.  Written 
notification of approval is to be submitted by the investigator to the sponsor monitor 
before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature.  This written approval must consist 
of a completed sponsor IRB Approval Form or written documentation from the IRB 
containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval 
from the IRB, or a designee, must be received by the sponsor before implementation.  


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This written approval will consist of a completed IRB Approval form or written 
documentation from the IRB containing the same information. 


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16. REFERENCES 
 
1 
Andreassen TN, Klepstad P, Davies A, et al. Influences on the pharmacokinetics of oxycodone: a 
multicentre cross-sectional study in 439 adult cancer patients. Eur J Clin Pharmacol. 
2011;67:493-506. 
2 
Benziger DP, Kaiko RF, Miotto JB, Fitzmartin RD, Reder RF, Chasin M. Differential effects of 
food on the bioavailability of controlled-release oxycodone tablets and immediate-release 
oxycodone solution. J Pharm Sci. 1996;85:407-410. 
3 
Davis MP, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman R. Normal-release and 
controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support 
Care Cancer. 2003;11:84-92. 
4 
Foral PA, Ineck JR, Nystrom KK. Oxycodone accumulation in a hemodialysis patient. South Med 
J. 2007;100:212-214. 
5 
Gammaitoni AR, Davis MW. Comparison of the pharmacokinetics of oxycodone administered in 
three Percocet formulations. J Clin Pharmacol. 2002;42:192-197. 
6 
Grönlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Olkkola KT, Laine K. Exposure to oral 
oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by 
inhibition of CYP2D6 alone. Br J Clin Pharmacol. 2010;70:78-87. 
7 
Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and 
pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998;64:603-611. 
8 
Kapil R, Nolting A, Roy P, Fiske W, Benedek I, Abramowitz W. Pharmacokinetic properties of 
combination oxycodone plus racemic ibuprofen: two randomized, open-label, crossover studies in 
healthy adult volunteers. Clin Ther. 2004;26:2015-2025. 
9 
Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic 
patients undergoing renal transplantation. J Clin Anesth. 1996;8:13-18. 
10 
Kokubun H, Fukawa M, Matoba M, Hoka S, Yamada Y, Yago K. Pharmacokinetics and variation 
in the clearance of oxycodone and hydrocotarnine in patients with cancer pain. Biol Pharm Bull. 
2007;30:2173-2177. 
11 
Kummer O, Hammann F, Moser C, Schaller O, Drewe J, Krähenbühl S. Effect of the inhibition of 
CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin 
Pharmacol. 2011;67:63-71. 
12 
Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and 
pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active 
metabolites. Clin Pharmacol Ther. 2006;79:461-479. 
13 
Leow KP, Cramond T, Smith MT. Pharmacokinetics and pharmacodynamics of oxycodone when 
given intravenously and rectally to adult patients with cancer pain. Anesth Analg. 1995;80:296-
302. 
14 
Leow KP, Smith MT, Watt JA, Williams BE, Cramond T. Comparative oxycodone 
pharmacokinetics in humans after intravenous, oral, and rectal administration. Ther Drug Monit. 
1992;14:479-484. 
15 
Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother. 
2004;18:17-30. 


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16 
Olesen AE, Upton R, Foster DJ, et al. A pharmacokinetic and pharmacodynamic study of oral 
oxycodone in a human experimental pain model of hyperalgesia. Clin Pharmacokinet. 
2010;49(:817-827. 
17 
Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of 
its use in the management of pain. Curr Med Res Opin. 2008;24:175-192. 
18 
Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the 
pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010;160:907-918. 
19 
Staahl C, Upton R, Foster DJ, et al. Pharmacokinetic-pharmacodynamic modeling of morphine 
and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. 
J Clin Pharmacol. 2008;48:619-631. 
20 
Pokela ML, Anttila E, Seppälä T, Olkkola KT. Marked variation in oxycodone pharmacokinetics 
in infants. Paediatr Anaesth. 2005;15:560-565. 
21 
El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 
6 months to 7 years old. J Clin Pharmacol. 2006;46:433-442. 
22 
Kalso E. Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative 
children. Br J Clin Pharmacol. 1995;39:214-215. 
23 
Kokki H, Rasanen I, Lasalmi M, et al. Comparison of oxycodone pharmacokinetics after buccal 
and sublingual administration in children. Clin Pharmacokinet. 2006;45:745-754. 
24 
Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanpera I. Pharmacokinetics of 
oxycodone after intravenous, buccal, intramuscular and gastric administration in children. Clin 
Pharmacokinet. 2004;43:613-622. 
25 
Olkkola KT, Hamunen K, Seppälä T, Maunuksela EL. Pharmacokinetics and ventilatory effects of 
intravenous oxycodone in postoperative children. Br J Clin Pharmacol. 1994;38:71-76. 
26 
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. Jan 1 2011;89(1):46-53. 
27 
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size 
when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2011. doi: 
10.1177/0091270011422812 
28 
Aleissa S, Parsons D, Grant J, Harder J, Howard J. Deep wound infection following pediatric 
scoliosis surgery: incidence and analysis of risk factors. Can J Surg. 2011;54:263-269. 
29 
Canavese F, Turcot K, De Rosa V, de Coulon G, Kaelin A. Cervical spine sagittal alignment 
variations following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. 
Eur Spine J. 2011;20:1141-1148. 
30 
Hwang SW, Samdani AF, Tantorski M, et al. Cervical sagittal plane decompensation after surgery 
for adolescent idiopathic scoliosis: an effect imparted by postoperative thoracic hypokyphosis. J 
Neurosurg Spine. 2011;15:491-496. 
31 
Ipp L, Flynn P, Blanco J, et al. The findings of preoperative cardiac screening studies in 
adolescent idiopathic scoliosis. J Pediatr Orthop. 2011;31:764-766. 
32 
Oto M, Shah SA, Mohammed MA, Rogers KJ, Yorgova P, Holmes L. Effectiveness and safety of 
posterior titanium instrumentation in children with adolescent idiopathic scoliosis: a prospective 
study. Eklem Hastalik Cerrahisi. 2011;22:124-128. 
33 
Charney RL, Yan Y, Schootman M, Kennedy RM, Luhmann JD. Oxycodone versus codeine for 
triage pain in children with suspected forearm fracture: a randomized controlled trial. Pediatr 
Emerg Care. 2008;24:595-600. 


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34 
Kokki H, Lintula H, Vanamo K, Heiskanen M, Eskelinen M. Oxycodone vs placebo in children 
with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of 
analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med. 2005;159:320-325. 
35 
Miner JR, Moore J, Gray RO, Skinner L, Biros MH. Oral versus intravenous opioid dosing for the 
initial treatment of acute musculoskeletal pain in the emergency department. Acad Emerg Med. 
2008;15:1234-1240. 
36 
Sharar SR, Carrougher GJ, Selzer K, O'Donnell F, Vavilala MS, Lee LA. A comparison of oral 
transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care 
Rehabil. 2002;23:27-31. 
37 
Malviya S, Merkel SI, Shayevitz JR, Voepel-Lewis T. The FLACC: a behavioral scale for scoring 
postoperative pain in young children. Pediatric Nursing. 1997;23(3):293-297. 
 


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17. ATTACHMENTS 
17.1 Schedule of Events 
Table 2: 
Schedule of Events 
 
 
 
 
STUDY PROCEDURES 
Screening 
(Day −14 to −1) 
OUTPATIENT 
HOSPITALIZATION 
 
 
End of 
Study/Early 
Discontinuationc 
Predose 
Check-in 
(Day −1) a,b 
Treatment 
(Day 1, 
Time Zero)b 
Informed consent/assent 
X 
 
 
 
Eligibility (inclusion/exclusion) 
X 
X 
 
 
Prior medication assessment 
X 
X 
 
 
Medical history 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
Temperature 
X 
 
X 
 
Pulse Oximetry 
 
 
X 
 
FLACC 
 
 
X 
 
Physical examinationd 
X 
 
 
 
Clinical laboratory testse 
X 
 
 
X 
Serum pregnancy test (females) 
X 
X 
 
 
Urine drug screenf 
X 
 
 
 
Safety 12-lead 
electrocardiogram 
X 
 
 
 
Study drug administration 
 
 
X 
 
Pharmacokinetic sampling 
 
 
X 
 
Adverse event assessment 
 
 
Xg 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
a 
The predose check-in (Day −1) can be performed the same day as surgery (Day 1).  At the predose 
check-in, eligibility and prior medications will be reviewed and updated as needed.  Medical history 
will be recorded if it was not completed at Screening. 
b 
Day −1 and Day 1 are adjacent and not separated by a Day 0. 
c 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 24 hours after dosing 
with Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do so, 
subjects will be discharged from the study.  
d 
The physical examination will include measurements of height, weight, and body mass index. 
e 
Complete blood count with differential and clinical chemistry will be performed at Screening and End 
of Study/Early Discontinuation.  Human immunodeficiency virus antibody screen, hepatitis B and 
hepatitis C screen, and urinalysis will be performed at Screening only. 
f 
The urine drug screen will test for drugs of abuse (amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, and benzodiazepines) and alcohol (not required for subjects less 
than 2 years of age). 


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g 
During the study, subjects will be asked about adverse events.  If an adverse event occurs, clinic staff 
may advise the subject to remain at the hospital until a decision is made that it is safe for the subject to 
be discharged. 


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17.2 Treatment Day Procedures 
Table 3: 
Treatment Day Procedures 
Time, related to 1st dose of 
Oxycodone Oral Solution 
Pre-
dose 
0 min 
5 min 
10 min 
15 min 
30  min 
45 min 
60 min 
1 hr   
15 min 
1 hr   
30 min 
1 hr   
45 min 
2 hr 
2 hr   
15 min 
2 hr   
30 min 
2 hr   
45 min 
Vital signs (BP, HR, Resp.) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pulse oximetrya 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (Under age 2) 
Xb 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (2 to <17) 
Xb 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
Study drug administrationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FLACCd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time, related to 1st dose of 
Oxycodone Oral Solution 
3 hr 
3 hr   
15 min 
3 hr   
30 min 
3 hr   
45 min 
4 hr 
6 hr 
8 hr 
10 hr 
12 hr 
14 hr 
16 hr 
18 hr 
20 hr 
22 hr 
24 hr 
Vital signs (BP, HR, Resp.)a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrya 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
PK sampling (Under age 2) 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
PK sampling (2 to <17) 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
X 
Study drug administrationc 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
FLACCd 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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a Pulse oximetry will begin as soon as possible following the procedure and will continue until 8 hours after the last study dose.  The following timepoints will be captured in the CRF: 5, 10, 30 and 60 
minutes, 2 hours, then every 2 hours until 8 hours after the last dose of Oxycodone Oral Solution. 
b Blood samples for pharmacokinetic assessment will be collected at the predose time point (within 15 minutes of dosing);  
c The study drug will be administered after the surgery when subjects have been postoperatively cleared to transition to oral pain medication in place of the standard analgesic medication.  If pain control 
is inadequate with study drug, the investigator may administer rescue medication for breakthrough pain after dosing. 
d The FLACC will also be administered prior to the subject receiving each rescue dose of Fentanyl. 
e AEs and Con Meds will be monitored throughout the course of the study. 
 
 
 


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17.3 Investigator’s Agreement 
 
PROTOCOL NUMBER: 
2012O004 
PROTOCOL TITLE: 
A PHASE IV STUDY TO EVALUATE THE SAFETY 
AND PHARMACOKINETICS OF OXYCODONE 
ORAL SOLUTION IN PEDIATRIC AND 
ADOLESCENT SUBJECTS 
FINAL PROTOCOL: 
[25 Apr 2013] 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein.  I will 
ensure that all subinvestigators and other study staff members have read and understand 
all aspects of this protocol.  I agree to cooperate fully with VistaPharm, Inc. and Lehigh 
Technologies, Inc., or designee during the study.  I will adhere to all FDA, ICH, and 
other applicable regulations and guidelines regarding clinical trials on an investigational 
product during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 


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17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) 
 
Categories 
Scoring 
 
0 
1 
2 
Face 
No particular 
expression or smile 
Occasional grimace 
or frown, withdrawn, 
disinterested 
Frequent to constant 
quivering chin, 
clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, 
tense 
Kicking, or legs 
drawn up 
Activity 
Lying quietly, 
normal position, 
moves easily 
Squirming, shifting 
back and forth, tense 
Arched, rigid or 
jerking 
Cry 
No cry, (awake or 
asleep) 
Moans or whimpers; 
occasional complaint 
Crying steadily, 
screams or sob, 
frequent complaints 
Consolability 
Content, relaxed 
Reassured by 
occasional touching, 
hugging or being 
talked to, distractible 
Difficult to console 
or comfort 
 


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18. APPENDICES 
A. Address List 
B. OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved Label 
and Full Prescribing Information 


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A. 
Address List 
18.1.1 
Sponsors 
Name: 
VistaPharm, Inc. 
Address: 
7256 Ulmerton Road 
 
Largo, FL 33771 
Phone: 
(727) 530-1633 
Fax: 
(727) 531-5427 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
Name: 
Lehigh Valley Technologies, Inc. 
Address: 
514 North 12th Street 
 
Allentown, PA 18102 
Phone: 
(610) 782-9780 
 
 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
18.1.2 
Clinical Research Organization 
Name: 
Cognitive Research Corporation 
Address: 
200 Central Avenue, Suite 1230 
 
Saint Petersburg, FL 33703 
Phone: 
(727) 897-9000 
Fax: 
(727) 897-9009 
Project Manager: 
Eva M. Kemper, MSHS 
Director, Clinical Projects 
 
 


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B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information 
 


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11 July 2013 
Version:  v7.1 
 
 
 
 
 
 
 
A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY 
OF OXYCODONE ORAL SOLUTION IN PEDIATRIC AND ADOLESCENT 
SUBJECTS 
 
PROTOCOL DATE: 
Version 7.1, Final 25 April 2013 
Amendment #1, 11 July 2013 
 
SPONSORED BY: 
VistaPharm, Inc. 
7256 Ulmerton Road 
Largo, FL 33771 
Phone:  (727) 530-1633 
 
 
Lehigh Valley Technologies, Inc. 
514 North 12th Street 
Allentown, PA 18102 
Phone:  (610) 782-9780 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
Cognitive Research Corporation
200 Central Avenue, Suite 1230 
St. Petersburg, FL 33701 
Phone: (727) 897-9000 
Fax: (727) 897-9009 
 
This study will be performed in compliance with Good Clinical Practices and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to 
the extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, 
or as required by law.  Persons to whom this information is disclosed should be informed that this 
information is confidential and may not be further disclosed without the express permission of 
VistaPharm, Inc. 
 


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1. PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Sponsor Contact Information 
Role in Study 
Name 
Address and  
Telephone Number 
Clinical Study Leader 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
Clinical Operations Leader 
Eva M. Kemper, 
MSHS 
Director, Clinical 
Projects  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-690-2667 
Physician 
Lawrence Blob, M.D.  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 410-262-1908 
24-hour Emergency Contact 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
 
Secondary Contact: 
Deborah Lees, R.N.  
Assistant Project 
Manager 
 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-943-8249 
 


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2. SYNOPSIS 
 
PRODUCT NAME 
OXYCODONE ORAL SOLUTION 
PROTOCOL NUMBER 
2012O004 
DEVELOPMENT PHASE 
PHASE IV 
PROTOCOL TITLE 
A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS 
AND SAFETY OF OXYCODONE ORAL SOLUTION IN PEDIATRIC 
AND ADOLESCENT SUBJECTS 
INDICATION 
Moderate to severe pain 
PRINCIPAL 
INVESTIGATOR 
This is a multicenter study.  The lead Principal Investigator will be: 
Senthilkumar Sadhasivam, M.D. 
Cincinnati Children’s Hospital Medical Center 
3333Burnet Avenue, MLC2001 
Cincinnati, OH 45229 
PLANNED STUDY 
SITES 
Up to 10 sites in the US. 
 
OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to 
evaluate the safety of single and multiple doses of Oxycodone Oral 
Solution in pediatric and adolescent subjects for postoperative pain.   
STUDY DESIGN 
This is a Phase IV study to characterize the pharmacokinetics and to 
evaluate the safety of Oxycodone Oral Solution administered to pediatric 
and adolescent subjects for postoperative pain.  It is an open-label, 
multicenter study conducted at up to 10 sites.  Subjects will be enrolled 
preoperatively up to 14 days before surgery with the expectation that they 
will require intravenous (IV) access after the surgery for at least 24 hours 
and postoperative analgesia with an opiate-level medication.  After dosing 
with Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 to 17, and a dose to be 
determined based on pharmacokinetic (PK) modeling from the interim 
analyses for subjects under age 2), subjects will be carefully monitored for 
safety.  A total of 110 pediatric and adolescent male or female subjects will 
be enrolled, including a minimum of 20 subjects under age 2 (5 subjects 
ages 0 to <2 months, 5 subjects ages 2 to <6 months, and 10 subjects ages 6 
months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 
13 to <17 years.  Subjects within each age group will be evenly distributed 
by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 
to 12 years and 10 ages 13 to <17 years have completed the study.  The 
interim analysis will include PK, pulse oximetry readings, vital sign 
measurements, adverse events (AEs) and concomitant medications.  The 
dose of Oxycodone Oral Solution that the subjects ages 6 months to <2 
years will receive will be based on PK modeling from the interim analysis. 
An additional interim analysis will be run after at least half of the subjects 
aged 6 months to <2 years have completed the study.  The interim analysis 
will include PK, pulse oximetry readings, vital sign measurements, AEs 
and concomitant medications.  The dose of Oxycodone Oral Solution that 


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the subjects ages 0 to <2 months and 2 months to <6 months will receive 
will be based on PK modeling from the interim analysis. 
The study will consist of a Screening period within 14 days of surgery; a 
predose check-in (Day −1); a treatment period after surgery (Day 1, 
Time Zero); and an End-of-Study assessment.  The total duration of the 
study, excluding Screening, will be approximately 1 full day. 
Eligible subjects who provide assent (7 to <17 years old) and whose 
parent(s) or legal guardian(s) provide consent as required will have study 
assessments performed at Screening.  Following surgery, subjects will 
receive standard care, including parenteral analgesia with a nonoxycodone, 
nonoxymorphone medication that will not interfere with the measurement 
or metabolism of oxycodone.  At this time (during Day −1), they will have 
a predose check-in to have eligibility confirmed.   
After subjects ages 2 to <17 have been postoperatively cleared to transition 
to oral pain medication, Oxycodone Oral Solution will be administered at 
Time Zero of Day 1 in place of the standard analgesic medication.  The first 
10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, who will 
be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  If pain control is inadequate with Oxycodone 
Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) 
every 4 hours as rescue medication for breakthrough pain after dosing.  Use 
of other rescue pain medication is permissible in accordance with hospital 
pain management guidelines or facilities standard of care.  Any rescue 
medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to 
oral pain medication, they will receive a single dose of Oxycodone Oral 
Solution at Time Zero of Day 1 in place of the standard analgesic 
medication.  The dose will be determined based on PK modeling from the 
interim analyses.  If pain control is inadequate with Oxycodone Oral 
Solution, as indicated by a score of moderate to severe (4-10) on the 
FLACC, the subject will be given Fentanyl via Nurse-Controlled Analgesia 
(NCA).  The Fentanyl will be provided by the study site pharmacy. 
Subjects will undergo an End-of-Study assessment at least 24 hours after 
receiving the first dose of Oxycodone Oral Solution.  At that time, if the 
study staff determines that it is safe to do so, subjects will be discharged 
from the study. 
Safety will be assessed by monitoring AEs, clinical laboratory test results, 
vital sign measurements, temperature, pulse oximetry, and physical 
examination findings. 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) will be 
used to measure pain prior to and 20, 40, 60, 90, 120, 180, and 240 minutes 
after the dose of Oxycodone Oral Solution in subjects under age 2.  The 
FLACC will also be administered prior to the subject receiving each dose 
of Fentanyl. 
Serial blood samples for PK analysis will be collected for the determination 
of plasma concentrations of oxycodone and its metabolites (noroxycodone, 
oxymorphone and noroxymorphone) prior to the first dose (within 15 
minutes of dosing); 5 (between 3-8 min), 15 (between 10-20 min), 30 
(between 25-35 min), and 60 (between 50-70 min) minutes after dosing; 


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and 2 (between 110-130 min), 4 (between 3-5 hrs), 6 (between 4-7 hrs), 8 
(between 6-10 hrs), 12 (between 12-18 hrs), and 24 (between 22-24 hrs) 
hours after the first dose of Oxycodone Oral Solution. For subjects under 
age 2, serial blood samples for PK analysis will be collected prior to the 
first dose (within 15 minutes of dosing); 15 (between 10-20 min), 30 
(between 25-35 min), and 60 (between 50-70 min) minutes after dosing; 
and 2 (between 110-130 min), 6 (between 4-7 hrs), 12 (between 12-18 hrs), 
and 24 (between 22-24 hrs) hours after dosing. 
PLANNED NUMBER OF 
SUBJECTS 
A total of 110 subjects, including a minimum of 20 subjects under age 2, 30 
ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to <17 years, are 
planned for this study to ensure adequate evaluation of the safety and PK 
profiles of Oxycodone Oral Solution. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria  
A subject will be eligible for inclusion in the study if he or she meets the 
following criteria: 
1. Is male or female <17 years of age at the time of dosing. 
2. Subject 2 to <17 years of age, be in at least the 25% for weight 
according to the Center for Disease Control pediatric growth charts 
and weighs at least 28 lb at the time of dosing with study drug. 
3. Is generally healthy as documented by medical history (except for the 
condition for which the procedure is being performed); physical 
examination (including, but not limited to, the cardiovascular, 
gastrointestinal, respiratory, and central nervous systems); vital sign 
assessments; electrocardiogram; clinical laboratory assessments; and 
general observations.  Has a negative serum pregnancy test at 
Screening and predose check-in for females of childbearing potential. 
4. Is an outpatient for a surgical procedure and is expected to remain 
hospitalized for at least 24 hours after dosing with study drug. 
5. Is anticipated to have postsurgical pain requiring a parenteral 
analgesic regimen using a short-acting opioid analgesic and is 
anticipated to be switched to an oral opioid for at least 1 dose 
(according to institution standard of care). 
6. Has an indwelling access catheter for blood sampling. 
7. Agrees to comply with all protocol requirements.  If not old enough, 
the legally responsible parent(s) or legal guardian(s) must agree to 
comply with all protocol requirements. 
8. Has been informed of the nature of the study and informed consent 
and assent (as appropriate) have been obtained from the legally 
responsible parent(s) or legal guardian(s) and the subject, 
respectively, in accordance with institutional review board 
requirements. 
Exclusion criteria  
A subject will be excluded from the study if he or she meets the following 
criteria: 
1. Has the presence or history of a clinically significant disorder 
involving the cardiovascular, respiratory, renal, gastrointestinal, 
immunologic, hematologic, endocrine, or neurologic system(s) or 
psychiatric disease (except for the condition for which the procedure 
is being performed) as determined by the clinical investigator. 


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2. Has any clinical laboratory test result outside the normal range. 
3. Had a clinically significant illness, except for the condition for which 
the procedure is being performed, in the 28 days before dosing with 
study drug as determined by the clinical investigator. 
4. Is a lactating or breastfeeding female. 
5. Uses any medication known to be an inhibitor or inducer of CYP3A4 
within 14 days (for inhibitors such as the azole-antifungal agents 
voriconazole and ketoconazole, macrolide antibiotics such as 
erythromycin, and protease inhibitors such as ritonavir) or 28 days 
(for inducers such as rifampin, carbamazepine, and phenytoin) of 
dosing with study drug. Use of all other prescription medications, 
except required pre-op medications and birth control, is prohibited 
within 3 days of dosing with study drug.  Use of any over-the-counter 
medications (including herbal or dietary supplements and therapeutic 
doses of vitamins), except for required pre-op medications, is 
prohibited within 24 hours of dosing with study drug, with the 
exception of topical spermicide.  Use of St. John’s wort is prohibited 
from 28 days before dosing until 14 days after dosing.  Standard daily 
dose multivitamins (nontherapeutic doses) may be taken until 
enrollment into the study but will be restricted during the study. 
6. Consumes alcohol-, caffeine-, or xanthine-containing products within 
8 hours before dosing and during periods when blood samples are 
collected. 
7. Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-
containing products within 5 days of dosing.  Fruit juices, with the 
exception of apple and grape, will be prohibited during the study. 
8. Is a smoker or has used nicotine or nicotine-containing products 
within 30 days of dosing. 
9. Has a history of alcohol or drug addiction or abuse within the last 
year. 
10. Subject 2 to <17 years of age, has a positive urine test result for drugs 
of abuse (amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, and benzodiazepines) or alcohol 
at Screening (not required for subjects less than 2 years of age). 
11. Donated blood within 28 days or plasma within 14 days of dosing or 
plans to donate them within 4 weeks after completing the study. 
12. Has a history of relevant drug allergies, food allergies, or both 
(i.e., allergy to oxycodone, allergy to related drugs, or any significant 
food allergy that could interfere with the study). 
13. Is intolerant to direct venipuncture. 
14. Received an investigational drug within 28 days of dosing. 
15. Has taken oxycodone or oxymorphone within the 48 hours before 
anticipated dosing with study drug. 
16. Is not suitable for entry into the study in the opinion of the 
investigator. 
INVESTIGATIONAL 
PRODUCT 
Oxycodone Oral Solution provided by VistaPharm, Inc., supplied in 
500-mL bottles.  Oxycodone Oral Solution contains 4.5 mg of oxycodone 
free base per 5 mL (5 mg oxycodone HCl/5 ml) and the following inactive 
ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid anhydrous 


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US Pharmacopeia (USP), glycerin natural USP, sorbitol solution 70% USP, 
FD&C Red #40 , raspberry flavor, and water. 
TREATMENT REGIMEN 
Each subject in the 2 to 6, 7 to 12 and 13 to <17 age groups will receive a 
dose of Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to 17) in place of the 
standard analgesic dose after being postoperatively cleared to transition to 
oral pain medication.  The first 10 subjects in each of these age groups, 
who will be included in the first interim analysis, will only receive 1 dose 
of Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  Each subject under age 2 will receive a single 
dose of Oxycodone Oral Solution.  The dose will be determined based on 
PK modeling from the interim analyses.  Oxycodone Oral Solution will be 
administered with an oral medication syringe. 
CRITERIA FOR 
EVALUATION 
Pharmacokinetic endpoints: 
• 
Area under the plasma concentration versus time curve from 
Time Zero to the last measurable concentration (AUC0-t) 
• 
Area under the plasma concentration versus time curve from 
Time Zero to infinity (AUC0-inf) 
• 
Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• 
Maximum measured plasma concentration (Cmax) 
• 
Time of the maximum measured plasma concentration (Tmax) 
• 
Apparent first-order terminal elimination rate constant (Kel) 
• 
Apparent first-order terminal elimination half-life (t1/2) 
• 
Apparent clearance (CL/F) 
• 
Volume of distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
Safety endpoints: 
Safety will be assessed by the monitoring and recording of AEs; clinical 
laboratory results (including hematology, serum chemistry, and urinalysis); 
vital sign measurements (systolic and diastolic blood pressures, heart rate, 
and respiratory rate); temperature; pulse oximetry; and physical 
examination findings. 
 Exploratory Study Endpoints: 
Analgesic sparing will be the surrogate efficacy endpoint in children under 
age 2.The Total FLACC Score will be an exploratory endpoint in children 
under age 2. 
STATISTICAL 
METHODS 
Analysis Populations 
PK Population: the PK population will consist of all subjects who receive 
study drug and have at least 1 measureable plasma concentration. 
Safety Population: the safety population will consist of all subjects who 
receive study drug. 
Subject Characteristics and Disposition 
For categorical variables, frequencies and percentages will be presented.  
Continuous variables will be summarized using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). 


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Baseline demographic and background variables will be summarized.  The 
number of subjects who enroll in the study and the number and percentage 
of subjects who complete the study will be presented.  The frequency and 
percentage of subjects who withdraw or discontinue from the study, along 
with the reason for withdrawal or discontinuation, will also be summarized. 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and 
noroxymorphone) plasma concentrations will be listed and summarized.  
Each subject’s oxycodone plasma concentrations will be graphed by using 
both a normal scale y-axis and a logarithmic scale y-axis.  Mean oxycodone 
plasma concentrations will also be graphed using scheduled elapsed 
sampling times for both the normal and logarithmic scale y-axis. 
Pharmacokinetic parameters will be listed for each subject and 
summarized.  Key PK parameters will be contrasted with adult values from 
the literature. 
Other PK analyses may be performed as appropriate. 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities 
and will be summarized overall.  Adverse events will also be summarized 
by severity and relationship to study drug.  Serious AEs and AEs leading to 
discontinuation of study drug will also be summarized. 
Actual values and changes from Baseline for clinical laboratory results, 
pulse oximetry, and vital sign measurements will be summarized at each 
time point using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) or shift tables where appropriate.  Physical 
examination findings will be presented in a listing. 
  
SAMPLE SIZE 
DETERMINATION 
The evaluable sample size for this study is powered to target a 
95% confidence interval within 60% and 140% of the geometric mean 
estimates of clearance and volume of distribution for oxycodone with at 
least 80% power. 
Because of an anticipated dropout rate of 33%, a recruited sample size of 
30 subjects is considered sufficient to ensure 20 evaluable subjects to assess 
the PK profiles of Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, 
the trial will enroll 110 subjects to gather adequate safety information in 
the pediatric/adolescent patient population. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods will be as 
follows: 
Screening is up to 14 days. 
The total study duration for each subject is 1 full day, excluding Screening. 
The maximum treatment duration for each subject is 1 full day. 


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3. TABLE OF CONTENTS 
 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................9 
3.1 
List of Tables .....................................................................................................12 
4. 
LIST OF ABBREVIATIONS.....................................................................................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1 
Background and Rationale ................................................................................15 
5.1.1 Indication and Usage .............................................................................15 
5.1.2 Description ............................................................................................15 
5.1.3 Pharmacodynamics ................................................................................16 
5.1.4 Pharmacokinetics ...................................................................................16 
5.1.4.1 
Absorption .................................................................................16 
5.1.4.2 
Distribution ...............................................................................16 
5.1.4.3 
Metabolism ................................................................................17 
5.1.4.4 
Elimination ................................................................................17 
5.1.5 Clinical Experience ...............................................................................17 
5.1.6 Study Rationale .....................................................................................17 
5.2 
Summary of Potential Risks and Benefits .........................................................17 
5.2.1 Potential Risks .......................................................................................17 
5.2.2 Benefits ..................................................................................................18 
6. 
OBJECTIVE ...............................................................................................................19 
7. 
STUDY DESIGN .......................................................................................................19 
7.1 
Overall Study Design and Plan .........................................................................19 
7.2 
Discussion of Study Design ..............................................................................21 
7.3 
Study Sites .........................................................................................................21 
7.4 
Point of Contact .................................................................................................21 
8. 
SUBJECT POPULATION .........................................................................................21 
8.1 
Selection of Study Population ...........................................................................21 
8.1.1 Inclusion Criteria ...................................................................................21 
8.1.2 Exclusion Criteria ..................................................................................22 
8.2 
Removal of Subjects from Therapy or Assessment ..........................................23 
9. 
STUDY TREATMENTS............................................................................................24 
9.1 
Method of Assigning Subjects to Treatment Groups ........................................24 


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9.1.1 Under Age 2 ..........................................................................................24 
9.1.2 Ages 2 to <17 ........................................................................................24 
9.2 
Identification of Investigational Products .........................................................24 
9.3 
Treatment Administered ....................................................................................24 
9.3.1 Under Age 2 ..........................................................................................24 
9.3.2 Ages 2 to <17 ........................................................................................24 
9.4 
Storage ...............................................................................................................25 
9.5 
Labeling .............................................................................................................25 
9.6 
Drug Accountability ..........................................................................................25 
9.7 
Blinding and Unblinding Treatment Assignment .............................................25 
9.8 
Selection of Dose in the Study ..........................................................................25 
9.9 
Selection of Timing of Dose for Each Subject ..................................................26 
9.10 Treatment Compliance ......................................................................................26 
9.11 Permitted and Prohibited Therapies ..................................................................26 
9.11.1 Permitted Therapies ...............................................................................26 
9.11.2 Prohibited Therapies ..............................................................................27 
9.12 Rescue Medication ............................................................................................27 
10. STUDY PROCEDURES ............................................................................................28 
10.1 Screening (Day −14 to Day −1) ........................................................................28 
10.2 Predose Check-in (Day −1) ...............................................................................28 
10.3 Open-Label Treatment (Day 1, After Surgery) .................................................28 
10.4 End-of-Study/Early Discontinuation .................................................................30 
11. STUDY ASSESSMENTS ..........................................................................................31 
11.1 Pharmacokinetics ...............................................................................................31 
11.1.1 Sample Collection .................................................................................31 
11.1.2 Blood Volumes ......................................................................................32 
11.1.3 Sample Processing .................................................................................32 
11.1.4 Transport of Samples .............................................................................33 
11.1.5 Analytical Procedures ............................................................................33 
11.1.5.1 Bioanalytical Sample Analyses .................................................33 
11.1.5.2 Bioanalytical Methodology .......................................................33 
11.2 Safety .................................................................................................................34 
11.2.1 Adverse Events ......................................................................................34 
11.2.1.1 Adverse Event Definitions ........................................................34 
11.2.1.2 Eliciting and Documenting Adverse Events .............................35 
11.2.1.3 Reporting Adverse Events.........................................................35 


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11.2.1.4 Follow-up of Adverse Events....................................................38 
11.2.2 Laboratory Safety Assessments .............................................................39 
11.2.3 Vital Signs .............................................................................................39 
11.2.4 Pulse Oximetry ......................................................................................39 
11.2.5 Electrocardiogram .................................................................................39 
11.2.6 Physical Examination ............................................................................39 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) ..........................40 
12. STATISTICAL METHODS .......................................................................................40 
12.1 General Considerations .....................................................................................40 
12.2 Analysis Populations .........................................................................................40 
12.3 Statistical Analyses ............................................................................................40 
12.3.1 Subject Disposition and Demographic Characteristics .........................40 
12.3.2 Pharmacokinetic Analyses ....................................................................41 
12.3.3 Safety Analyses .....................................................................................41 
12.3.4 Exploratory Analyses ............................................................................41 
12.3.5 Interim Analyses ....................................................................................41 
12.4 Sample Size Determination ...............................................................................42 
13. STUDY CONDUCT ...................................................................................................42 
13.1 Sponsor and Investigator Responsibilities ........................................................42 
13.1.1 Sponsor Responsibilities .......................................................................42 
13.1.2 Investigator Responsibilities .................................................................42 
13.2 Site Initiation .....................................................................................................43 
13.3 Screen Failures ..................................................................................................44 
13.4 Study Documents ..............................................................................................44 
13.4.1 Good Clinical Practice Documents .......................................................44 
13.4.2 Case Report Forms ................................................................................44 
13.4.3 Source Documents .................................................................................45 
13.5 Data Quality Control .........................................................................................45 
13.5.1 Monitoring Procedures ..........................................................................45 
13.5.2 Data Management ..................................................................................46 
13.5.3 Quality Assurance/Audit .......................................................................46 
13.6 Study Termination .............................................................................................47 
13.6.1 Regular Study Termination ...................................................................47 
13.6.2 Premature Study Termination ...............................................................47 
13.7 Study Site Closure .............................................................................................47 
13.7.1 Record Retention ...................................................................................47 


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13.7.2 Sample Retention ..................................................................................48 
13.8 Changes to the Protocol .....................................................................................48 
13.9 Use of Information and Publication ..................................................................48 
14. FINAL CLINICAL STUDY REPORT ......................................................................49 
15. ETHICAL AND LEGAL CONSIDERATIONS ........................................................49 
15.1 Declaration of Helsinki and Good Clinical Practice .........................................49 
15.2 Subject Information and Informed Consent ......................................................49 
15.3 Approval by Institutional Review Board ...........................................................49 
16. REFERENCES ...........................................................................................................51 
17. ATTACHMENTS .......................................................................................................54 
17.1 Schedule of Events ............................................................................................54 
17.2 Treatment Day Procedures ................................................................................56 
17.3 Investigator’s Agreement ..................................................................................58 
17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) ...............................59 
18. APPENDICES ............................................................................................................60 
A. 
Address List .......................................................................................................61 
18.1.1 Sponsors ................................................................................................61 
18.1.2 Clinical Research Organization .............................................................61 
B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information ............................................................62 
 
3.1 
List of Tables 
Table 1: 
Sponsor Contact Information ..................................................................2 
Table 2: 
Schedule of Events ................................................................................54 
Table 3: 
Treatment Day Procedures ....................................................................56 


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4. LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AUC 
Area under the curve 
AUC0-inf 
Area under the concentration-time curve from Time Zero to infinity 
AUC0-t 
Area under the concentration-time curve from Time Zero to the last 
measurable concentration 
Cmax  
Observed maximum plasma concentration 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG  
Electrocardiogram 
EDC 
Electronic data capture 
FDA  
Food and Drug Administration 
FLACC 
Face, Legs, Activity, Cry, Consolability Scale 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonisation 
IRB  
Institutional review board 
ITT 
Intention-to-Treat Population 
IV 
Intravenous 
Kel 
Elimination rate constant  
kg 
Kilogram 
L 
Liter 
lbs 
Pounds 
mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
NCA 
Nurse-Controlled Analgesia 
PK 
Pharmacokinetic 
RPM 
Revolutions per minute 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
Standard of care 


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t1/2 
Apparent elimination half-life 
TBV 
Total blood volume 
Tmax 
Time of maximum concentration 
USP 
United States Pharmacopeia 
 


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5. INTRODUCTION 
5.1 
Background and Rationale 
5.1.1 
Indication and Usage 
Oxycodone (4, 5α-epoxy-14-hydroxy-3-methoxy-17methylmorphinan-6-one 
hydrochloride) is a semisynthetic opioid that has been in clinical use since 1917 and 
approved for use in the US since 1950.  Developed by VistaPharm, Inc., oxycodone 
hydrochloride (HCl) US Pharmacopeia (USP) oral solution, 5 mg per 5 mL, is an 
immediate-release oral formulation of oxycodone hydrochloride indicated for the 
management of moderate to severe acute and chronic pain where the use of an opioid 
analgesic is appropriate.  This product was approved by the Food and Drug 
Administration (FDA) on January 12, 2012 (application New Drug Application 201194).  
In addition, Lehigh Valley Technologies, Inc. has developed Oxycodone Hydrochloride 
Oral Solution available as a 100 mg/5 mL (20 mg/mL) concentration which is indicated 
for use in opioid-tolerant patients only. This product was approved by the Food and Drug 
Administration (FDA) on October 20, 2010 (application New Drug Application 200535). 
The results of the study described with the current protocol will be utilized to meet 
regulatory requirements for both VistaPharm, Inc. and Lehigh Valley Technologies, Inc.    
Oxycodone HCl is currently available in the US in a number of other forms and 
combinations.  Oxycodone is a Schedule II controlled substance. The VistaPharm, Inc., 
oxycodone hydrochloride (HCl) (USP) oral solution, 5 mg per 5 mL, will be utilized for 
the purposes of this protocol. 
5.1.2 
Description 
Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium 
alkaloid thebaine.  Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is 
considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). 
Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-
17methylmorphinan-6-one hydrochloride and has the following structural formula: 
 


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5.1.3 
Pharmacodynamics 
Oxycodone is a semisynthetic narcotic with multiple actions qualitatively similar to those 
of morphine; the most prominent of these involve the central nervous system and organs 
composed of smooth muscle.  The principal actions of therapeutic value of oxycodone are 
analgesia and sedation. 
Oxycodone is similar to codeine and methadone in that it retains at least one-half of its 
analgesic activity when administered orally. 
Additional detailed information on the pharmacodynamic properties of oxycodone 
hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the Approved Label 
and Full Prescribing Information (Appendix B). 
5.1.4 
Pharmacokinetics 
5.1.4.1 Absorption 
About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in 
comparison with a parenteral dose.  This high oral bioavailability (compared to other oral 
opioids) is due to lower presystemic metabolism, first-pass metabolism, or both of 
oxycodone. 
A single-dose food effect study was conducted in normal adult volunteers using the 
5 mg/5 mL solution.  The concurrent intake of a high fat meal was shown to enhance the 
extent (a 27% increase in the area under the plasma concentration versus time curve 
[AUC]) but not the rate of oxycodone absorption from the oral solution.  In addition, food 
caused a delay in the time of maximum concentration (Tmax) (1.25 to 2.54 hours). 
5.1.4.2 Distribution 
Following intravenous (IV) administration, the volume of distribution for oxycodone was 
2.6 L/kg.  Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%.  
Oxycodone has been found in breast milk. 


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5.1.4.3 Metabolism 
Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, 
and their glucuronides.  The major circulating metabolite is noroxycodone with an AUC 
ratio of 0.6 relative to that of oxycodone.  Oxymorphone is present in the plasma only in 
low concentrations.  The analgesic activity profile of other metabolites is not known at 
present. 
The formation of oxymorphone but not noroxycodone is mediated by CYP2D6 and as 
such its formation can, in theory, be affected by other drugs. 
5.1.4.4 Elimination 
Oxycodone and its metabolites are excreted primarily via the kidney.  The amounts 
measured in the urine have been reported as follows:  up to 19% was reported for free 
oxycodone; up to 50% was reported for conjugated oxycodone; 0% was reported for free 
oxymorphone; no greater than 14% was reported for conjugated oxymorphone; and both 
free and conjugated noroxycodone have been found in the urine but not quantified.  The 
total plasma clearance was 0.8 L/min for adults. 
Additional detailed information on the physical, chemical, and pharmaceutical properties 
of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the 
Approved Label and Full Prescribing Information (Appendix B). 
5.1.5 
Clinical Experience 
Oxycodone hydrochloride USP oral solution has been studied in adult populations, with a 
focus on pharmacokinetics, safety, and tolerability.  A total of 4 clinical pharmacokinetic 
(PK) and bioavailability studies have been conducted to support the development and 
labeling of oxycodone hydrochloride USP oral solution. 
In addition, there are a number of published studies in the medical literature that report on 
the pharmacokinetics of oxycodone in clinical and nonclinical settings, in a variety of 
doses and routes of administration.1-19 
5.1.6 
Study Rationale 
Despite published studies on dosing and pharmacokinetics in pediatric populations,20-25 
oxycodone has never received an official indication for use in children.  Pursuant to the 
Pediatric Research Equity Act (21 USC 355c), the FDA has requested that VistaPharm, 
Inc. and Lehigh Valley Technologies, Inc. conduct a postapproval and postmarketing 
(Phase IV) PK and safety study in subjects < 17 years of age. 
5.2 
Summary of Potential Risks and Benefits 
5.2.1 
Potential Risks 
The most frequently observed adverse events (AEs) reported with oxycodone include 
light headedness, dizziness, sedation, nausea, and vomiting.  These effects seem to be 
more prominent in subjects who can walk than in subjects who cannot walk, and some of 


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these adverse reactions may be alleviated if the subject lies down.  Other AEs include 
euphoria, dysphoria, constipation, skin rash, and pruritus. 
Additional detailed information on potential AEs and on specific warnings and 
precautions with the use of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, 
can be found in the Approved Label and Full Prescribing Information (Appendix B). 
Given that some of the subjects will be infants and young children, the effect of multiple 
blood draws can be considered a potential risk or adverse situation.  A published review 
of the safe limits of blood sample volumes in child health research suggests that existing 
guidelines specify limits ranging from 1% to 5% of total blood volume (TBV) over 
24 hours.  However, the limited available evidence that includes findings from 
nonrandomized studies shows a minimal risk with one-off sampling of up to 5% of 
TBV.26 
For subjects 2 <17 years of age, this protocol specifies a maximum of 11 serial blood 
samples of 0.5 mL each for a total of 5.5 mL, plus 2.5 mL each for standard clinical 
chemistry and hematology tests at Screening and End of Study.  In addition, up to 10 mL 
will be allotted as discard volume for the 11 PK samples and the final laboratory testing 
drawn through the indwelling catheter.  Existing blood draw guidelines for pediatric 
research suggest minimal risk is between 3% and 5% of total blood volume (TBV) over 
24 hours or on a single draw and TBV is generally estimated at 75-80 mL/kg.  For the 
smallest child permitted per protocol, 2 to <17 years of age (weight: 28 lbs or 12.7 kg), 
the TBV would be estimated at 952.5 ml. The maximum safe volume drawn would 
therefore be between 28 and 47 mL, based on minimal risk at 3-5% TBV over 24 hours.  
The required 10.5 mL plus up to 10 mL of discard volume, or a cumulative volume of 
20.5 mL, is well under the 3-5% of TBV guideline for the smallest eligible participant 
using the smallest estimation of TBV. 26 
For the child less than 2 years of age, there is a maximum of 8 serial blood samples of 0.5 
mL each for a total of 4.0 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 9 mL is under the 3-5% of 
TBV guideline. 
5.2.2 
Benefits 
The size of the test dose (0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 
0.07 mg/kg for ages 13 to 17, and a dose to be determined based on PK modeling from 
the interim analyses for subjects under age 2) is designed to provide adequate analgesia 
for moderate to severe pain in substituting for the routinely prescribed postoperative pain 
regimen according to the custom of the attending physician and the institutional standard 
of care (SOC). 
No other benefit is anticipated or expected for subjects participating in this study. 


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6. OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to evaluate the 
safety of single and multiple doses of Oxycodone Oral Solution in pediatric and 
adolescent subjects.   
7. STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a Phase IV study to characterize the pharmacokinetics and to evaluate the safety 
of Oxycodone Oral Solution administered to pediatric and adolescent subjects following 
a surgical procedure.  It is an open-label, multicenter study conducted at up to 10 sites.  
Subjects will be enrolled preoperatively up to 14 days before surgery with the expectation 
that they will require IV access after the surgery for at least 24 hours and postoperative 
analgesia with an opiate-level medication.  After dosing with Oxycodone Oral Solution 
(0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 
to 17, and a dose to be determined based on PK modeling from the interim analyses for 
subjects under age 2), subjects will be carefully monitored for safety.  A total of 
110 pediatric and adolescent male or female subjects will be enrolled, including a 
minimum of 20 subjects under age 2 (5 subjects ages 0 to <2 months, 5 subjects ages 2 to 
<6 months, and 10 subjects ages 6 months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 
12 years and 30 ages 13 to <17 years.  Subjects within each age group will be evenly 
distributed by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects under 
age 2 will receive will be based on PK modeling from the interim analysis.  
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on PK modeling from the interim analysis. 
The study will consist of a Screening period within 14 days of surgery; a predose 
check-in (Day −1); a treatment period after surgery (Day 1, Time Zero); and an 
End-of-Study assessment.  The total duration of the study, excluding Screening, will be 
approximately 1 full day. 
Eligible subjects who provide assent (7 to <17 years old) and whose parent(s) or legal 
guardian(s) provide consent as required will have study assessments performed at 
Screening.  Following surgery, subjects will receive standard care, including parenteral 
analgesia with a nonoxycodone, nonoxymorphone medication that will not interfere with 
the measurement or metabolism of oxycodone.  At this time (during Day −1), they will 
have a predose check-in to have eligibility confirmed.   


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After subjects ages 2 to <17 years have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of Day 1 in 
place of the standard analgesic medication.  The first 10 subjects in each of the 2 to 6, 7 
to 12 and 13 to <17 age groups, who will be included in the first interim analysis, will 
only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age groups enrolled in 
the study after the interim analysis is completed may receive additional doses every 4-6 
hours as needed.  If pain control is inadequate with Oxycodone Oral Solution, the 
investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 6 hours or an IV 
dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue medication for 
breakthrough pain after dosing.  Use of other rescue pain medication is permissible in 
accordance with hospital pain management guidelines or facilities standard of care.  Any 
rescue medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero of 
Day 1 in place of the standard analgesic medication.  The dose will be determined based 
on PK modeling from the interim analyses.  If pain control is inadequate with Oxycodone 
Oral Solution, as indicated by a score of moderate to severe (4-10) on the FLACC, the 
subject will be given Fentanyl via NCA.  The Fentanyl will be provided by the study site 
pharmacy. 
Water, Gatorade, Powerade, Pedialite, or Popsicles will be allowed for the first hour (1 
hour) following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study.  
Subjects will undergo an End-of-Study assessment at least 24 hours after dosing with 
Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do 
so, subjects will be discharged from the study.  Subjects who discontinue the study for 
any reason will not be replaced. 
Safety will be assessed, between time 0 and 24 hours post first study medication 
administration, by monitoring AEs, clinical laboratory test results, vital sign 
measurements, temperature, pulse oximetry, and physical examination findings. 
The FLACC will be used to measure pain prior to  and 20, 40, 60, 90, 120, 180, and 240 
minutes after the dose of Oxycodone Oral Solution in subjects under 2 years of age.  The 
FLACC will also be administered prior to the subject receiving each dose of Fentanyl. 
For subjects 2 to <17 years of age, serial blood samples for PK analysis will be collected 
for the determination of plasma concentrations of oxycodone at the predose time point 
(within 15 minutes of dosing); 5 (between 3-8 min), 15 (between 10-20 min), 30 
(between 25-35 min), and 60 (between 50-70 min) minutes after dosing; and 2 (between 
110-130 min), 4 (between 3-5 hrs), 6 (between 4-7 hrs), 8 (between 6-10 hrs), 12 
(between 12-18 hrs), and 24 (between 22-24 hrs) hours after the first dose of Oxycodone 
Oral Solution. For subjects under age 2, serial blood samples for PK analysis will be 
collected prior to the first dose (within 15 minutes of dosing); 15 (between 10-20 min), 
30 (between 25-35 min), and 60 (between 50-70 min) minutes after dosing; and 2 
(between 110-130 min), 6 (between 4-7 hrs), 12 (between 12-18 hrs), and 24 (between 
22-24 hrs) hours after dosing.  


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7.2 
Discussion of Study Design 
This is an open-label, nonrandomized, multicenter study designed to assess the 
pharmacokinetics and safety of the product oxycodone hydrochloride USP oral solution, 
5 mg per 5 mL, in pediatric and adolescent subjects <17 years of age following a surgical 
procedure and expected to require postoperative opioid analgesia and to require an 
indwelling IV catheter for a minimum of 24 hours after being cleared for oral intake.  
Target enrollment will be 110 subjects, including a minimum of 20 subjects under age 2 
(5 subjects ages 0 to <2 months, 5 subjects ages 2 to <6 months, and 10 subjects ages 6 
months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to <17 
years, to evaluate safety in the population.  Subjects within each age group will be evenly 
distributed by age and gender.  In addition, this sample size will allow for an adequate 
evaluable population according to published population PK studies in children21 and 
unofficial FDA guidance on sample size calculations based on estimates of clearance and 
volume of distribution.27  Recruitment projections are based on a review of recent reports 
of adolescent scoliosis surgery showing that major specialty surgical centers average 
10 to 20 patients per year in this age group.28-32 
7.3 
Study Sites 
The study will take place at up to 10 sites in the US. 
7.4 
Point of Contact 
A point of contact will be identified to provide subjects with information on the study, 
subject rights, and whom to contact in case of study-related injury. This information will 
be provided in the subject information and informed assent and consent forms. 
8. SUBJECT POPULATION 
8.1 
Selection of Study Population 
8.1.1 
Inclusion Criteria 
A subject will be eligible for inclusion in the study if he or she meets the following 
criteria: 
1 
Is male or female <17 years of age at the time of dosing. 
2 
Subject 2 to <17 years of age, be in at least the 25% for weight according to the 
Center for Disease Control pediatric growth charts and weighs at least 28 lb at the 
time of dosing with study drug. 
3 
Is generally healthy as documented by medical history (except for the condition for 
which the procedure is being performed); physical examination (including, but not 
limited to, the cardiovascular, gastrointestinal, respiratory, and central nervous 
systems); vital sign assessments; electrocardiogram (ECG); clinical laboratory 
assessments; and general observations.  Has a negative serum pregnancy test at 
Screening and predose check-in for females of childbearing potential. 


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4 
Is an outpatient for a surgical procedure and is expected to remain hospitalized for at 
least 24 hours after dosing with study drug. 
5 
Is anticipated to have postsurgical pain requiring a parenteral analgesic regimen by 
using a short-acting opioid analgesic and is anticipated to be switched to an oral 
opioid for at least 1 dose (according to institution standard of care). 
6 
Has an indwelling access catheter for blood sampling. 
7 
Agrees to comply with all protocol requirements.  If not old enough, the legally 
responsible parent(s) or legal guardian(s) must agree to comply with all protocol 
requirements. 
8 
Has been informed of the nature of the study, and informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, in accordance with institutional review 
board requirements. 
8.1.2 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets the following criteria: 
1 
Has the presence or history of a clinically significant disorder involving the 
cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, 
endocrine, or neurologic system(s) or psychiatric disease (except for the condition for 
which the procedure is being performed) as determined by the clinical investigator. 
2 
Has any clinical laboratory test result outside the normal range. 
3 
Has a clinically significant illness, except for the condition for which the procedure is 
being performed, in the 28 days before dosing with study drug as determined by the 
clinical investigator. 
4 
Is a lactating or breastfeeding female. 
5 
Uses any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) 
or 28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing 
with study drug. Use of all other prescription medications, except required pre-op 
medications and birth control, is prohibited within 3 days of dosing with study drug.  
Use of any over-the-counter medications (including herbal or dietary supplements and 
therapeutic doses of vitamins), except for required pre-op medications, is prohibited 
within 24 hours of dosing with study drug, with the exception of topical spermicide.  
Use of St. John’s wort is prohibited from 28 days before dosing until 14 days after 
dosing.  Standard daily dose multivitamins (nontherapeutic doses) may be taken until 
enrollment into the study but will be restricted during the study. 
6 
Consumes alcohol-, caffeine-, or xanthine-containing products within 8 hours before 
dosing and during periods when blood samples are collected. 


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7 
Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-containing 
products within 5 days of dosing.  Fruit juices, with the exception of apple and grape, 
will be prohibited during the study. 
8 
Is a smoker or has used nicotine or nicotine-containing products within 30 days of 
dosing. 
9 
Has a history of alcohol or drug addiction or abuse within the last year. 
10 Subject 2 to <17 years of age, has a positive urine test result for drugs of abuse 
(amphetamines, barbiturates, cannabinoids, cocaine metabolites, opiates, 
phencyclidine, and benzodiazepines) or alcohol at Screening (not required for 
subjects less than 2 years of age). 
11 Donated blood within 28 days or plasma within 14 days of dosing or plans to donate 
them within 4 weeks after completing the study. 
12 Has a history of relevant drug allergies, food allergies, or both (i.e., allergy to 
oxycodone, allergy to related drugs, or any significant food allergy that could 
interfere with the study). 
13 Is intolerant to direct venipuncture. 
14 Received an investigational drug within 28 days of dosing. 
15 Has taken oxycodone or oxymorphone within the 48 hours before anticipated dosing 
with study drug. 
16 Is not suitable for entry into the study in the opinion of the investigator. 
8.2 
Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from participation in this study at any time for any 
reason and without prejudice. 
The investigator may terminate a subject from the study at any time for lack of 
therapeutic effect that is intolerable to the subject or otherwise considered unacceptable, 
for intolerable or unacceptable AEs, intercurrent illness, noncompliance with study 
procedures, administrative reasons, or unsuitability for the study in the investigator’s 
opinion to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate case report form (CRF).  Whenever possible and reasonable, 
evaluations that were scheduled for study completion should be performed at the time of 
premature discontinuation. 
Subjects who discontinue from the study will not be replaced. 


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9. STUDY TREATMENTS 
9.1 
Method of Assigning Subjects to Treatment Groups 
9.1.1 
Under Age 2 
Subjects under age 2 who meet all eligibility criteria will receive a single dose of 
Oxycodone Oral Solution.  This will be an open-label study and does not require 
randomization. 
9.1.2 
Ages 2 to <17 
Subjects ages 2 to <17 who meet all eligibility criteria will be scheduled to receive single 
or multiple doses of Oxycodone Oral Solution.  This will be an open-label study and does 
not require randomization. 
9.2 
Identification of Investigational Products 
The study drug is Oxycodone Oral Solution (5 mg/5 mL) manufactured by VistaPharm 
(Largo, FL).  Oxycodone Oral Solution is a red solution intended for oral administration. 
Oxycodone Oral Solution will be supplied in 500-mL bottles.  Oxycodone Oral Solution 
contains 4.5 mg of oxycodone free base per 5 mL (5 mg oxycodone HCl/5 ml) and the 
following inactive ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid 
anhydrous USP, glycerin natural USP, sorbitol solution 70% USP, FD&C Red #40, 
raspberry flavor, and water. 
VistaPharm will provide an adequate supply of study drug to the sites. 
Ketorolac for injection (15 mg/mL or 30 mg/mL), Morphine Sulfate for injection (2 
mg/mL), and Fentanyl via NCA for use as a rescue medication will be provided by the 
study site pharmacy. Should other rescue medication be required they will be provided by 
the study site pharmacy. 
9.3 
Treatment Administered 
The study drug will be administered only to eligible subjects under the supervision of the 
investigator or identified subinvestigator(s). 
9.3.1 
Under Age 2 
Each subject will receive a single dose of Oxycodone Oral Solution in place of the 
standard analgesic dose after being postoperatively cleared to transition to oral pain 
medication.  The dose will be determined based on PK modeling from the interim 
analyses.  Oxycodone Oral Solution will be administered with an oral medication syringe. 
9.3.2 
Ages 2 to <17 
Each subject will receive a dose of Oxycodone Oral Solution (0.1 mg/kg for children 
ages 2 to 6, 0.08 mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to 17) in place of the 
standard analgesic dose after being postoperatively cleared to transition to oral pain 


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medication.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, 
who will be included in the first interim analysis, will only receive 1 dose of Oxycodone 
Oral Solution.  Subjects enrolled in the study after the interim analysis is completed may 
receive additional doses every 4-6 hours as needed.  Oxycodone Oral Solution will be 
administered with an oral medication syringe.   
9.4 
Storage 
Oxycodone Oral Solution will be stored in a locked facility with restricted access.  This 
may be a locked cabinet or room for which the number of keys is limited and in 
compliance with standards of the Drug Enforcement Administration for Schedule II 
narcotics.  Chain of custody of the study drug will be followed in accordance with the 
individual site’s standard procedures, which will be documented by the site and provided 
to the sponsor.  The study drug will be stored at controlled room temperature between 
20°C and 25°C (68°F-77°F).  The sponsor will provide to the site personnel instructions 
for the storage and return of used and unused study drug. 
9.5 
Labeling 
Each container of study drug will be labeled with study-specific information that meets 
all applicable regulatory requirements. 
9.6 
Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, 
or other disposition of study drug, including the date, quantity, batch or code number, and 
identification of subjects (subject number and initials) who received study drug.  The 
investigator will not supply study drug to any person except those named as 
subinvestigators on the FDA 1572, designated staff, and subjects in this study.  The 
investigator will not dispense study drug from any sites other than those listed on the 
FDA 1572.  Study drug may not be relabeled or reassigned for use by other subjects. 
Upon completion of the study, unused supplies of study drug will be reconciled by the 
investigator and returned to the sponsor as directed. 
9.7 
Blinding and Unblinding Treatment Assignment 
Not applicable. 
9.8 
Selection of Dose in the Study 
The published literature on treatment of pediatric pain with oxycodone reports doses 
ranging from 0.125 to 0.2 mg/kg, up to a maximum of 15 mg, for treatment of acute 
musculoskeletal pain, including suspected fractures in emergency room settings, for 
treatment of undifferentiated abdominal pain, and for pediatric burn wound care in 
outpatient clinics.33-36  A PK modeling has been conducted using the data derived from 
the 4 studies conducted in the adult population. Based on these population data, the test 
dose chosen for subjects ages 2 to 6 is 0.1 mg/kg, ages 7 to 12 is 0.08 mg/kg, ages 13 to 
17 is 0.07 mg/kg, and a dose to be determined based on PK modeling from the interim 
analyses for subjects under age 2, given when the subjects have been cleared for oral 


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intake and in place of the analgesic regimen (nonoxycodone and nonoxymorphone) 
prescribed postoperatively for subjects by their attending physicians according to 
institutional SOCs.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age 
groups, who will be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the study after the 
interim analysis is completed may receive additional doses every 4-6 hours as needed.   
The dose for subjects under age 2 will be determined based on PK modeling from the 
interim analyses. 
9.9 
Selection of Timing of Dose for Each Subject 
The design of the study and the timing of dosing were selected to provide the appropriate 
basis for assessing the PK parameters of oxycodone following administration of the first 
dose. 
9.10 Treatment Compliance 
All study drugs will be administered in the hospital by study personnel and recorded in 
the CRF.  Study personnel will confirm that the subject ingests the entire dose of study 
drug. 
The date and time of study drug administration will be recorded on the appropriate page 
of the CRF.  If a subject does not receive the study drug, the reason for the missed dose 
will be recorded. 
9.11 Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate CRF. The 
medication name, dose, including frequency, date, and indication for use must be 
recorded.  Time of rescue medication will also be recorded. The medical monitor should 
be notified in advance of (or as soon as possible after) any instances in which prohibited 
therapies or rescue medications are administered.  Medications and therapies that are 
considered necessary for the subject’s welfare and will not interfere with the response to 
the study medication may be given at the discretion of the investigator. 
9.11.1 
Permitted Therapies 
Concomitant medications (with the exceptions described in Section 9.11.2) are allowed, 
but should be limited to only those medications considered necessary. 
Nausea and vomiting are common opioid-induced AEs for which subjects do develop a 
tolerance. Subjects who undergo surgery requiring opioid analgesia for an extended 
period of time may develop these AEs.  Therefore, it is expected that some subjects will 
need to be given an antiemetic. Any antiemetic used during treatment with study drug 
should be recorded as a concomitant medication. 


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9.11.2 
Prohibited Therapies 
Use of any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) or 
28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing with 
study drug through the end of the study is prohibited. Use of all other prescription 
medications, with the exception of allowable pre-op medications and birth control, is 
prohibited within 3 days of dosing with study drug.  Use of any monoamine oxidase 
inhibitor is prohibited until 14 days after the final dose of study drug. 
Use of any over-the-counter medications (including herbal or dietary supplements and 
therapeutic doses of vitamins), except for allowable pre-op medications, is prohibited 
within 24 hours of dosing with study drug, with the exception of topical spermicide.  Use 
of St. John’s wort is prohibited from 28 days before dosing until 14 days after dosing.  
Standard daily dose multivitamins (nontherapeutic doses) may be taken until enrollment 
into the study but will be restricted during the study.   
Restrictions: 
Females of childbearing potential must be practicing abstinence or using a medically 
acceptable form of contraception (e.g., intrauterine device, hormonal birth control, or 
double-barrier method).  For the purpose of this study, all females who are menstruating 
will be considered to be of childbearing potential unless they are biologically sterile or 
surgically sterile for more than 1 year. 
Consumption of alcohol-, caffeine-, or xanthine-containing products within 8 hours 
before dosing and during periods when blood samples are collected is prohibited.  
Consumption of grapefruit, grapefruit products, Seville oranges, or pomelo-containing 
products is prohibited within 5 days of dosing with study drug.  All types of fruit juices, 
with the exception of apple and grape, and fruit-containing popsicles will be prohibited 
during the study. 
Subjects who smoke or use nicotine or nicotine-containing products within 30 days of 
Screening will be excluded from study participation. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for 
continuation in the study at the discretion of the sponsor, investigator, medical monitor, 
or other authority. 
9.12 Rescue Medication 
In subjects ages 2 to <17 years, if pain control is inadequate with Oxycodone Oral 
Solution, the investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 
6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue 
medication for breakthrough pain after dosing. Use of other rescue pain medication is 
permissible in accordance with hospital pain management guidelines or facilities standard 
of care.  Any rescue medications used will be provided by the study site pharmacy. 


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In subjects under age 2, if pain control is inadequate with Oxycodone Oral Solution, as 
indicated by a score of moderate to severe (4-10) on the FLACC, the subject will be 
given Fentanyl via NCA.  The Fentanyl will be provided by the study site pharmacy. 
10. STUDY PROCEDURES 
Subjects’ legally responsible parent(s) or legal guardian(s) will provide written informed 
consent and subjects will provide written informed assent (as appropriate) before any 
study-related procedures are initiated, including the cessation of prohibited concomitant 
therapy. 
Table 2 (Section 17) presents the schedule of events to be performed during the study. 
10.1 Screening (Day −14 to Day −1) 
Subjects must be screened within 14 days before enrollment in the study.  The following 
procedures will be performed at Screening: 
• Obtain written informed consent and assent (as appropriate). 
• Review inclusion and exclusion criteria. 
• Collect demographic information. 
• Record medical history, including prior and current therapies (e.g. prescription 
and nonprescription medications). 
• Perform a physical examination including weight, height, body mass index, and 
vital signs (blood pressure, heart rate, respiratory rate, and oral temperature).   
• Perform serum pregnancy test for all females of childbearing potential. 
• Perform urine drug screen (Section 11.2.2), excluding subjects < 2 years of age. 
• Perform ECG. This may occur at the screening visit or at any time prior to study 
medication dosing. 
• Collect blood and urine samples for clinical laboratory tests (complete blood 
count with differential, clinical chemistry, serology, and urinalysis) (Section 
11.2.2). 
10.2 Predose Check-in (Day −1) 
The predose check-in (Day −1) can be performed the same day as surgery (Day 1) at 
which time eligibility and prior medications will be reviewed and updated as needed.  
Medical history will be recorded, if it was not completed at Screening, and vital signs 
will be obtained.  Following surgery, subjects will receive standard care, including 
parenteral analgesia with a nonoxycodone, nonoxymorphone medication that will not 
interfere with the measurement or metabolism of oxycodone. 
10.3 Open-Label Treatment (Day 1, After Surgery) 
The following procedures will be performed on Day 1: 
• Measure blood pressure, heart rate, and respiratory rate before dosing (within 
90 minutes) with Oxycodone Oral Solution and every 15 minutes for 4 hours after 


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dosing, then every 2 hours until 24 hours after the first dose of Oxycodone Oral 
Solution. 
• Measure temperature every 2 hours for 24 hours after the first dose of Oxycodone 
Oral Solution. 
• Continuous pulse oximetry beginning as soon as possible following procedure 
through 8 hours after the last study dose of Oxycodone Oral Solution.  The following 
timepoints will be captured in the CRF: 5, 10, 30 and 60 minutes, 2 hours, then every 
2 hours until 8 hours after the last study dose of Oxycodone Oral Solution. 
• Assess pain in subjects under 2 years of age by using the FLACC prior to and 20, 40, 
60, 90, 120, 180, and 240 minutes after the first dose of Oxycodone Oral Solution.  
The FLACC will also be administered prior to the subject receiving each dose of 
Fentanyl. 
• Record concomitant medication use. 
• Assess and record AEs prior to dosing and throughout the remainder of Day 1. 
• For subjects 2 to <17 years of age, collect serial blood samples for PK analysis at the 
predose time point (within 15 minutes of dosing); 5 (between 3-8 min), 15 (between 
10-20 min), 30 (between 25-35 min), and 60 (between 50-70 min) minutes after 
dosing; and 2 (between 110-130 min), 4 (between 3-5 hrs), 6 (between 4-7 hrs), 8 
(between 6-10 hrs), 12 (between 12-18 hrs), and 24 (between 22-24 hrs) hours after 
the first dose of Oxycodone Oral Solution. For subjects under age 2, serial blood 
samples for PK analysis will be collected prior to the first dose (within 15 minutes of 
dosing); 15 (between 10-20 min), 30 (between 25-35 min), and 60 (between 50-70 
min) minutes after dosing; and 2 (between 110-130 min), 6 (between 4-7 hrs), 12 
(between 12-18 hrs), and 24 (between 22-24 hrs) hours after dosing. 
• After subjects ages 2 to <17 have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of 
Day 1 in place of the standard analgesic medication.  The first 10 subjects in each of 
the 2 to 6, 7 to 12 and 13 to <17 age groups, who will be included in the first interim 
analysis, will only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age 
groups enrolled in the study after the interim analysis is completed may receive 
additional doses every 4-6 hours as needed.  If pain control is inadequate with 
Oxycodone Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 
hours as rescue medication for breakthrough pain after dosing.  Use of other rescue 
pain medication is permissible in accordance with hospital pain management 
guidelines or facilities standard of care. 
• After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero 
of Day 1 in place of the standard analgesic medication.  The dose will be determined 
based on PK modeling from the interim analyses.  If pain control is inadequate with 


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Oxycodone Oral Solution, as indicated by a score of moderate to severe (4-10) on the 
FLACC, the subject will be given Fentanyl via NCA. 
Water, Gatorade, Powerade, and Popsicles will be allowed for the first hour (1 hour) 
following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study. 
10.4 End-of-Study/Early Discontinuation 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 
24 hours after dosing with Oxycodone Oral Solution. 
The following procedures will be performed at the End-of-Study/ Early Discontinuation 
visit: 
• Measure vital signs (blood pressure, heart rate, and respiratory rate). 
• Clinical laboratory testing (complete blood count with differential and clinical 
chemistry). 
• Record concomitant medications. 
• Record AEs. 
After these procedures are performed, the study staff will determine whether it is safe for 
the subject to be discharged from the study. 


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11. STUDY ASSESSMENTS 
11.1 Pharmacokinetics 
Blood samples for PK assessments in the subjects 2 to <17 years of age will be collected 
at the predose time point (within 15 minutes of the first dose of Oxycodone Oral 
Solution); 5 (between 3-8 min), 15 (between 10-20 min), 30 (between 25-35 min), and 60 
(between 50-70 min) minutes after dosing; and 2 (between 110-130 min), 4 (between 3-5 
hrs), 6 (between 4-7 hrs), 8 (between 6-10 hrs), 12 (between 12-18 hrs), and 24 (between 
22-24 hrs) hours after the first dose of Oxycodone Oral Solution. For subjects under age 
2, serial blood samples for PK analysis will be collected prior to the first dose (within 15 
minutes of dosing); 15 (between 10-20 min), 30 (between 25-35 min), and 60 (between 
50-70 min) minutes after dosing; and 2 (between 110-130 min), 6 (between 4-7 hrs), 12 
(between 12-18 hrs), and 24 (between 22-24 hrs) hours after dosing. Time Zero is the 
time of the first dose of Oxycodone Oral Solution. 
The following PK parameters will be calculated: 
• Area under the plasma concentration versus time curve from Time Zero to the last 
measurable concentration (AUC0-t) 
• Area under the plasma concentration versus time curve from Time Zero to infinity 
(AUC0-inf) 
• Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• Maximum measured plasma concentration (Cmax) 
• Time of the maximum measured plasma concentration (Tmax) 
• Apparent first-order terminal elimination rate constant (Kel) 
• Apparent first-order terminal elimination half-life (t1/2) 
• Apparent clearance (CL/F) 
• Volume of Distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
11.1.1 
Sample Collection 
Blood collection will be performed using an existing indwelling access catheter (arterial 
or venous noted on CRF) at the start of the study (the use of Emla at the insertion site is 
permitted).  All catheter lines should be appropriately flushed per institutional SOC 
before each blood draw.  The 0.5-mL blood samples will be obtained and placed into 
2.0-mL K3 ethylenediamine tetra-acetic acid tubes at each blood collection time point.  
The labels for all biological sample collection and storage containers will contain, at a 
minimum, the subject's number, protocol number, collection date, and scheduled 
collection time (study hour). 


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Study Visit/Phase 
Amount Collected 
(mL) 
Number of 
Samples 
Collected 
Total Amount 
Collected per 
Subject (mL) 
Screening Serum Chemistry and Hematologya 
2.5 mL 
1 
2.5 mL 
Pharmacokinetics (2 to <17 years old) or 
0.5 mL 
11 
5.5 mL 
    Pharmacokinetics (<2 years old) 
0.5 mL 
8 
4.0 mL 
End of Study Serum Chemistry and 
Hematology 
2.5 mL 
1 
2.5 mL 
Grand Total 
-- 
-- 
14.0 – 20.5 mLb 
a Where possible, results from clinical laboratory tests performed as part of the standard of care (SOC) will be used for study 
purposes.  A separate blood draw for the clinical laboratory test portion of this protocol will occur only if the clinical laboratory 
tests as part of the SOC will not be available to coincide with the approximate time scheduled by the protocol.  Preoperative or 
intraoperative (collected before the incision) test results must be available for review by the investigator before enrolling any 
subject into the study.  Procedures for blood draws should follow institutional SOC. 
b The total includes up to 10-mL discard volume for all 11 pharmacokinetic and laboratory testing samples, for the 2 to <17 year 
olds.  Total blood volume drawn for research purposes must not exceed 3% of subject’s total blood volume, which is assumed to be 
75 mL/kg.  
11.1.2 
Blood Volumes 
Existing blood draw guidelines for pediatric research suggest minimal risk is between 3% 
and 5% of total blood volume (TBV) over 24 hours or on a single draw, and TBV is 
generally estimated at 75-80 mL/kg.  For the smallest child permitted per protocol from 
ages 2 to <17 years (weight: 28 lbs or 12.7 kg), the TBV would be estimated at 952.5 ml. 
The maximum safe volume drawn would therefore be between 28 and 47 mL, based on 
minimal risk at 3-5% TBV over 24 hours.  The required 10.5 mL plus up to 10 mL of 
discard volume, or a cumulative volume of 20.5 mL, is well under the 3-5% of TBV 
guideline for the smallest eligible participant using the smallest estimation of TBV.26 For 
the child less than 2 years of age, there is a maximum of 8 serial blood samples of 0.5 mL 
each for a total of 4.0 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 9 mL is under the 3-5% of 
TBV guideline. 
11.1.3 
Sample Processing 
Immediately after collection, the tube will be gently inverted several times to mix the 
anticoagulant with the blood sample.  The plasma fraction will be separated by placing 
the collection tube into a refrigerated centrifuge (4°C to 8°C) for 10 minutes at 
approximately 1500g or 3000 RPM.  The plasma fraction will be withdrawn by pipette 
and placed into polypropylene freezing tubes in 2 approximately equal aliquots.  All 
sample collection and freezing tubes will be clearly labeled in a manner that identifies the 
subject and the collection time.  Labels will be fixed to the freezing tubes in a manner 
that will prevent the label from becoming detached after freezing.  All plasma samples 
will be placed into a freezer at approximately −20°C (± 10°C) or below until transfer or 
shipment to the bioanalytical laboratory. The time between sample collection and freezer 
storage should not exceed 90 minutes.  The additional blood draws for the purposes of 
pharmacokinetic assessment in this study do not pose more than a minor risk to the 
subjects. 


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11.1.4 
Transport of Samples 
The clinic staff will inventory the samples that are to be shipped to the bioanalytical 
laboratory.  Each shipment will contain a complete set of samples.  The second set of 
samples will not be shipped until receipt of the first shipment is confirmed.  The 
inventory record will accompany the frozen plasma samples as per standard operating 
procedures. 
For sample shipment requiring a third party courier, the samples will be packed in ample 
dry ice within a styrofoam container to ensure the samples will remain frozen for at least 
72 hours and will be shipped via express delivery to the bioanalytical facility.  Written 
notification of sample shipment will be communicated to the bioanalytical facility and the 
sponsor.  The samples will be tracked to assure arrival in a safe and timely manner. 
The shipment will be accompanied by logs showing the name of the study drug, protocol 
number, and the subject numbers and samples included in the shipment.  Documentation 
noting what the condition of the samples upon arrival at the bioanalytical laboratory is 
and whether the amount of dry ice remaining is adequate or inadequate should be 
returned to the clinic. 
The samples will be shipped frozen to: 
PPD - Houston 
10550 Rockley Road, Suite 150 
Houston, TX 77099, USA 
11.1.5 
Analytical Procedures 
11.1.5.1 Bioanalytical Sample Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be measured using a validated liquid chromatography–mass 
spectrometry assay method.  The validated detection range for oxycodone is 0.2 to 
125 ng/mL in human plasma. 
Samples from subjects who withdraw consent/assent or are dropped from the study will 
not be analyzed unless otherwise requested by the sponsor. 
Samples from subjects who have been dropped from the study because of emesis 
according to PPD’s standard operating procedures will not be analyzed. 
11.1.5.2 Bioanalytical Methodology 
The bioanalytical method, assay validation, and bioanalytical report for this study will be 
provided by the bioanalytical investigator.  Full validation of a sensitive assay for the 
appropriate analytes in biological fluid, including precision, accuracy, reproducibility, 
and selectivity will be included in the final report.  The bioanalytical report will include 
the stability of the frozen samples, limit of quantitation, recovery, and a summary of the 
standard curves. 


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11.2 Safety 
Safety will be assessed during the study by the monitoring and recording of AEs, clinical 
laboratory test results (hematology, biochemistry, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, and respiratory rate), 
temperature, pulse oximetry, and physical examination findings. 
11.2.1 
Adverse Events 
11.2.1.1 Adverse Event Definitions 
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation patient administered a pharmaceutical product that does not necessarily 
have a causal relationship with the product.  An AE can therefore be any unfavorable and 
unintended sign (including a new, clinically important abnormal laboratory finding), 
symptom, or disease temporally associated with the product, whether or not it is related to 
the product. 
Preexisting diseases or conditions will not be considered AEs unless there is an increase 
in the frequency or severity, or a change in the quality, of the disease or condition.  
Worsening of a preexisting condition is considered an AE. 
An expected AE is one for which the nature or severity is consistent with the known AE 
profile of the product.  For an investigational drug, the known information is contained in 
the investigator brochure.  For a marketed drug, the known information is in the current 
package insert. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current investigator brochure or package insert.  For example, hepatic necrosis would be 
unexpected (greater severity) if the investigator brochure or package insert only listed 
elevated hepatic enzymes or hepatitis.  Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the investigator brochure or 
package insert only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a 
known, already documented adverse reaction constitute unexpected AEs.  Examples 
include acute renal failure as an expected adverse reaction with a subsequent new 
occurrence of interstitial nephritis and hepatitis with a first occurrence of fulminate 
hepatitis. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly 
• Is an important medical event 


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Medical and scientific judgment should be used in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent another of the outcomes listed in the 
definition previously.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study 
drug or a hospital admission for a diagnostic evaluation of an AE does not qualify the 
condition or event as an SAE.  A newly diagnosed pregnancy in a subject who has 
received a study drug is not considered an SAE unless it is suspected that the study drug 
interacted with a contraceptive method and led to the pregnancy; however, the medical 
monitor should be made aware of a newly diagnosed pregnancy as soon as possible after 
site notification.  A congenital anomaly in an infant born to a mother who was exposed to 
the study drug during pregnancy is an SAE. 
11.2.1.2 Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 11.2.1.1) are recorded in the CRF and reported to the medical monitor 
(Section 11.2.1.3).  Adverse events will be collected from the time of the first dose of 
Oxycodone Oral Solution through the End of Study or Early Discontinuation visit. 
At each visit, subjects will be asked a standard question to elicit any medically related 
changes in their well-being.  They will also be asked if they have had any accidents, used 
any new medications, or changed concomitant medication regimens (both prescription 
and over-the-counter medications).  In addition to subject observations, AEs will be 
documented from any data collected on the AE page of the CRF (e.g., clinical laboratory 
values, physical examination findings, and ECG changes) or other documents that are 
relevant to subject safety. 
11.2.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the 
CRF.  Information to be collected includes drug treatment, type of event, time of onset, 
dose, investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome.  Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, reactions to concurrent medications, or progression of disease states must also 
be reported.  All AEs will be followed to adequate resolution.  The latest version of the 
Medical Dictionary of Regulatory Activities will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 


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The investigator or designee must report any AE that meets the criteria for an SAE 
(Section 11.2.1.1) to the medical monitor within 24 hours of first becoming aware of the 
event by telephone.  At the time of first notification, the investigator or designee should 
provide at a minimum the following information if available: 
• Protocol number 
• Subject’s study identification and initials 
• Subject’s date of birth 
• Date of dose of study drug 
• Time and date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
Within 24 hours of the initial telephone notification, the investigator must fax a written 
SAE report form to the medical monitor.  Any missing or additional relevant information 
about the SAE should be provided in a written follow-up SAE report form.  The 
investigator should also ensure that any additional information requested about the event 
(e.g., hospital reports, autopsy reports) is provided as soon as it is available. 
The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of the institutional review board (IRB). 
The following contact information is to be used for SAE reporting: 
 
Thomas J. Hochadel, Pharm.D. 
Cognitive Research Corporation 
200 Central Ave, Suite 1230 
Saint Petersburg, FL 33701 
Telephone: 727-897-9000 
Cell: 727-515-1334 
Fax: 727-897-9000 
11.2.1.3.1 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which it affects the subject’s 
daily activities.  Severity will be rated as mild, moderate, or severe using the following 
criteria: 
Mild: 
Is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere 
with usual activities of daily living. 
Moderate: 
Is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent 
risk of harm to the subject. 
Severe: 
Interrupts usual activities of daily living, significantly affects 


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clinical status, or may require intensive therapeutic intervention 
Changes in the severity of an AE should be documented to allow assessment of the 
duration of the event at each level of intensity to be performed.  Adverse events 
characterized as intermittent require documentation of onset and duration of each 
episode. 
11.2.1.3.2 Assessment of Relationship 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will 
be characterized using the following classification and criteria: 
Not related: 
An AE with sufficient evidence to accept that there is no causal 
relationship to administration of study drug (e.g., no temporal 
relationship because the study drug was administered after the 
onset of the event, an investigation shows that study drug was 
not administered, another cause was proven.) 
Unlikely related: 
An AE, including a clinical laboratory test abnormality, with a 
temporal relationship to administration of study drug that makes 
a causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
Possibly related: 
An AE with a reasonable time sequence to administration of 
study drug but that could also be explained by concurrent 
disease or other drugs or events.  Information on drug 
withdrawal may be lacking or unclear. 
Related: 
An AE occurring in a plausible time relationship to 
administration of study drug and that cannot be explained by a 
concurrent disease or other drugs or events.  The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 
11.2.1.3.3 Definition of Adverse Event Start Date, Stop Date, and Duration  
Start date: 
The date at which the AE is first noted 
Stop date: 
The date at which the AE is known to be resolved.  If it has not known 
to have stopped, then indicate “ongoing.” 
Duration: 
A time in days, hours, or minutes 


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11.2.1.3.4 Action(s) Taken 
Action(s) taken may consist of the following (as appropriate): 
None: 
No actions taken. 
Discontinued study 
drug: 
Study drug was permanently discontinued because of the AE. 
Treatment:  
Specified medication (to be listed on the concomitant medication 
chart) was used as a countermeasure. 
Others: 
Other actions, such as an operative procedure, were required 
because of the AE. 
11.2.1.3.5 Definition of Adverse Event Outcome at the Time of Last Observation 
The AE outcome at the time of last observation will be classified as “resolved,” “resolved 
with sequelae,” “ongoing,” “death,” “other,” or “unknown.” 
“Death” should only be selected as an outcome when the AE resulted in death.  If more 
than 1 AE is possibly related to the subject’s death, the outcome of death should be 
indicated for each such AE.  Although “death” is usually an event outcome, events such 
as sudden death or unexplained death should be reported as SAEs. 
11.2.1.4 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after dosing with study drug) to a 
satisfactory resolution or until the investigator deems the event to be chronic or not 
clinically significant or the subject to be stable.  All findings relevant to the final outcome 
of an AE must be reported in the subject’s medical record and recorded on the 
appropriate CRF. 


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11.2.2 
Laboratory Safety Assessments 
Samples for the following laboratory tests will be collected at the time points specified in 
the Schedule of Events (Section 17). 
Hematology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic transaminase), 
glucose (fasting), albumin, and total protein 
 
 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, 
microscopic urine analysis if dipstick positive 
Serum pregnancy 
test: 
Conducted for women of childbearing potential only 
Urine drug screen 
Includes amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, ethyl alcohol, and 
benzodiazepines 
Each safety laboratory assessment blood sample will be 2.5 mL in volume. The total 
amount of blood to be drawn will be a maximum of 19.5 mL per subject, including 11 
samples for PK assessments (0.5 mL each). 
11.2.3 
Vital Signs 
Vital signs, including heart rate, respiratory rate, and blood pressure will be measured at 
the time points specified in the schedule of events (Section 17) after the subject has been 
in a sitting position for 5 minutes.  Oral body temperature will also be measured. 
11.2.4 
Pulse Oximetry 
Continuous pulse oximetry will begin as soon as possible following the procedure and 
will continue until 8 hours after the last study dose of Oxycodone Oral Solution.  The 
following timepoints will be captured in the CRF: 5, 10, 30 and 60 minutes, 2 hours, then 
every 2 hours until 8 hours after the last study dose of Oxycodone Oral Solution. 
11.2.5 
Electrocardiogram 
An ECG will be performed pre-dose. This may occur at Screening or any time pre-dose, 
including intra-op. 
11.2.6 
Physical Examination 
A standard physical examination will be performed at Screening.  The examination will 
include assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, 


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cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities.  Interim 
physical examinations will be performed at the investigator’s discretion if necessary to 
evaluate AEs or clinical laboratory abnormalities. 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) (See Attachment 17.4) 
will be used to measure pain in subjects under age 2 prior to and 20, 40, 60, 90, 120, 180, 
and 240 minutes after the dose of Oxycodone Oral Solution.  The FLACC will also be 
administered prior to the subject receiving each dose of Fentanyl. 
The FLACC provides a simple framework for quantifying pain behaviors in children who 
are unable to verbalize the presence or severity of pain.37 
Additionally, time of rescue medication will also be evaluated. 
12. STATISTICAL METHODS 
12.1 General Considerations 
Descriptive statistics will be provided for all demographic, safety, and PK parameters.  
No formal statistical testing will be performed for this study. 
A statistical analysis plan (SAP) that describes the details of the analyses to be conducted 
will be written before database lock. 
12.2 Analysis Populations 
The following analysis populations are planned for this study: 
• PK Population: the PK population will consist of all subjects who receive the 
study drug and have at least 1 measureable plasma concentration. 
• Safety Population: the safety population will consist of all subjects who receive 
the study drug. 
12.3 Statistical Analyses 
12.3.1 
Subject Disposition and Demographic Characteristics 
For categorical variables, frequencies and percentages will be presented.  Continuous 
variables will be summarized by using descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized.  The number of 
subjects who enroll in the study and the number and percentage of subjects who complete 
the study will be presented.  The frequency and percentage of subjects who withdraw or 
discontinue from the study, along with the reason for withdrawal or discontinuation, will 
also be summarized. 


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12.3.2 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be listed and summarized.  Each subject’s oxycodone plasma 
concentrations will be graphed using both a normal scale y-axis and a logarithmic scale 
y-axis.  Mean oxycodone plasma concentrations will also be graphed using scheduled 
elapsed sampling times for both the normal and logarithmic scale y-axis. 
Pharmacokinetic parameters will be listed for each subject and summarized.  Key PK 
parameters will be contrasted with adult values from the previously conducted PK 
studies. 
Other PK analyses may be performed as appropriate. 
12.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and will be summarized 
overall.  Adverse events will also be summarized by severity and relationship to study 
drug.  Serious AEs and AEs leading to discontinuation of study drug will also be 
summarized. 
Actual values and changes from Baseline for clinical laboratory results, vital sign 
measurements, temperature, and pulse oximetry will be summarized at each time point 
using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) or shift tables where appropriate.  Physical examination findings will be 
presented in a listing. 
12.3.4 
Exploratory Analyses 
The change from baseline in total FLACC Score will be summarized at each time point.  
The total amount of Fentanyl will also be evaluated. 
12.3.5 
Interim Analyses 
 An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects ages 6 
months to <2 years will receive will be based on this interim analysis. 
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on PK modeling from the interim analysis. 


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12.4 Sample Size Determination 
The evaluable sample size for this study is powered to target a 95% confidence interval 
within 60% and 140% of the geometric mean estimates of clearance and volume of 
distribution for oxycodone with at least 80% power. 
Estimates of the coefficient of variation for the clearance and volume of distribution of 
oxycodone were 25.72% and 71.12%, respectively, and were based on estimated standard 
deviations of (log-transformed) clearance and volume as provided in a June 28, 2012 PK 
modeling technical report.  The above mentioned values for % coefficient of variation 
(%CV) are derived using the approximation: 
 
, 
 
where SD are the standard deviations given in the technical report, with values of 0.2531 
and 0.6398 for clearance and volume, respectively.  The methodology for samples size 
calculation is as given in Wang, et al.27   
Because of an anticipated dropout rate of 33%, a recruited sample size of 30 subjects is 
considered sufficient to ensure 20 evaluable subjects to assess the PK profiles of 
Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, the trial will 
enroll 110 subjects to gather adequate safety information. 
13. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the 
investigator and associated personnel prior to the study, periodic monitoring visits, and 
meticulous data management. 
13.1 Sponsor and Investigator Responsibilities 
13.1.1 
Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15).  The sponsor reserves the right to withdraw a subject from the study 
(Section 8.2), to terminate participation of a study site at any time (Section 13.7), or to 
discontinue the study (Section 13.6.2). 
The sponsor agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
13.1.2 
Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.3), the investigator indicates that he 
or she has carefully read the protocol, fully understands the requirements, and agrees to 


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conduct the study in accordance with the procedures and requirements described in this 
protocol. 
The investigator also agrees to conduct this study in accordance with all laws, 
regulations, and guidelines of the pertinent regulatory authorities, including and in 
accordance with the April 1996 ICH Guidance for Industry E6 Good Clinical Practice 
(GCP) and in agreement with the 1996 Version of the Declaration of Helsinki.  While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing 
the study and for ensuring compliance with the protocol and all applicable regulations 
and guidelines.  The investigator is responsible for maintaining a list of all persons that 
have been delegated study-related responsibilities (e.g., sub-investigators and study 
coordinators) and his or her specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, 
and their specific duties within the context of the study.  Investigators are responsible for 
providing the sponsor with documentation of the qualifications, GCP training, and 
research experience for themselves and their staff as required by the sponsor and the 
relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent 
person.  The investigator agrees, by written consent to this protocol, to cooperate fully 
with compliance checks by allowing access to all study documentation by authorized 
individuals. 
13.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving 
notification from the sponsor or its designee that the study can be initiated at the study 
site.  The study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed assent and consent. 
2. All GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 


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13.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study.  
Subjects may only be rescreened once 30 days or more after the original Screening visit.  
If a subject is eligible to enter the study after having previously failed screening, he or 
she will be assigned a new subject identification number. 
13.4 Study Documents 
All documentation and material provided by the sponsor for this study are to be retained 
in a secure location and treated as confidential material. 
13.4.1 
Good Clinical Practice Documents 
The GCP documents are listed below. 
• Signed original protocol; (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and sub-investigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• FDA Form 1572 
• Any other relevant GCP documents 
The GCP documents must be received from the investigator and reviewed and approved 
by the sponsor or designee before the study site can initiate the study and before the 
sponsor will authorize shipment of study drug to the study site.  Copies of the 
investigator’s GCP documents must be retained at the study site in a secure location.  
Additional documents, including a copy of the protocol and applicable amendment(s), the 
study drug, CRF completion guidelines, copies of regulatory references, copies of IRB 
correspondence, and study drug accountability records should also be retained as part of 
the investigator’s GCP documents.  It is the investigator’s responsibility to ensure that 
copies of all required GCP documents are organized, current, and available for 
inspection. 
13.4.2 
Case Report Forms 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to 
maintain accurate CRFs and source documentation as part of the case histories for all 
subjects whose legally responsible parent(s) or legal guardian(s) sign an informed 
consent form and subjects who sign assent (as appropriate). 
Case report forms are considered confidential documents and should be handled and 
stored accordingly.  The sponsor or its designee will provide the necessary training on the 
use of the specific CRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 


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To ensure data accuracy, CRF data for individual subject visits should be completed as 
soon as possible after the visit.  All requested information must be entered in the 
electronic data capture (EDC) system, if applicable, according to the completion 
guidelines provided by the sponsor or its designee. 
The CRFs may be signed by the investigator or a subinvestigator.  These signatures serve 
to attest that the information contained in the CRF is accurate and true. 
13.4.3 
Source Documents 
All information recorded in the EDC system must be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory notes, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files.  
Before the study starts, a list identifying any data to be recorded directly on the CRFs 
(i.e., no prior written or electronic record of data) and considered to be source data will 
be provided. 
Clinical laboratory data required by the protocol will be electronically transferred from 
the central laboratory to the sponsor or its designee. A paper copy of the laboratory 
results will be provided to the study site and should be retained with each subject’s 
source data. 
13.5 Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical study. 
13.5.1 
Monitoring Procedures 
The sponsor or designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines.  The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site 
at periodic intervals and maintain periodic communication.  The investigator agrees to 
allow the CRA(s) and other authorized sponsor personnel access.  The CRA(s) will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. While on site, the CRA(s) will review: 
• Regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• Consenting procedures 
• AE procedures 
• Storage and accountability of study drug and study materials 


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The CRA will ask for clarification or correction of any noted inconsistencies.  Procedures 
for correcting CRFs are described in the study manual.  As representatives of the sponsor, 
CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to meet 
with the CRA(s) during study site visits; to ensure that study staff is available to the 
CRA(s) as needed; to provide the CRA(s) access to all study documentation, to the 
clinical supplies dispensing and storage area; and to assist the monitors in their activities, 
if requested.  Further, the investigator agrees to allow the sponsor or designee auditors or 
inspectors from regulatory agencies to review records and to assist the inspectors in their 
duties, if requested. 
13.5.2 
Data Management 
The sponsor or designee will be responsible for activities associated with the data 
management of this study.  The standard procedures for handling and processing records 
will be followed per GCP and the sponsor’s or CRO’s standard operating procedures.  A 
comprehensive data management plan will be developed including a data management 
overview, database contents, annotated CRF, pre-entry review list, self-evident correction 
conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to 
data queries are described in the study manual. 
13.5.3 
Quality Assurance/Audit 
This study will be subject to audit by the sponsor or designee.  The audits will be 
undertaken to check compliance with GCP guidelines and will include a minimum of: 
• In-house study file audit 
• Audit of computer database quality control 
• Audit of clinical report quality control 
The sponsor or designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used 
for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities 
according to GCP guidelines.  The investigator agrees to cooperate with the auditor 
during the visit and will be available to supply the auditor with CRFs or other files 
necessary to conduct that audit.  Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, 
the investigator shall notify the sponsor immediately. 


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13.6 Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. 
13.6.1 
Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject 
out or last subject last visit) participating in the study.  Within 90 days of the end of the 
clinical study, the sponsor or designee will notify the IRB and regulatory authorities 
about the regular termination of the study as required. 
13.6.2 
Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by the sponsor, 
IRB, regulatory authorities, or the coordinating investigator.  A decision to prematurely 
terminate the study is binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, the sponsor or designee will 
notify the IRB and regulatory authorities as required. The sponsor or designee must 
clearly explain the reasons for premature termination. 
If the study is terminated prematurely, all investigators must inform their subjects and 
take care of appropriate follow-up and further treatment of subjects to ensure protection 
of the subjects’ interests.  Study sites may be asked to have all subjects currently 
participating in the study complete all of the assessments for the Early Termination visit. 
13.7 Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor may terminate 
participation of a study site at any time.  Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol, applicable regulations and guidelines, or both 
• Inadequate subject enrollment 
13.7.1 
Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until at 
least 2 years after the notification of submission of the final study report to regulatory 
authorities by the sponsor. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 


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After completing the study, the sponsor will be provided with the original CRFs or at 
least a legible copy and retain the documents at least 5 years after the completion of the 
study. 
One copy will remain with the investigator.  The investigator shall arrange for the 
retention of the subject identification codes, subject files, and other source data until at 
least 5 years after notification of submission of the final study report to the regulatory 
authorities by the sponsor.  These documents need to be retained for a longer period of 
time if required by applicable regulatory authorities or by agreement with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) 
shall be kept by the investigator for the maximum period of time permitted by the 
hospital, institution, or private practice. 
13.7.2 
Sample Retention 
Samples may be used for purposes related to this research.  The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision 
has been made that none of the samples needs to be reanalyzed.  In addition, identifiable 
samples can be destroyed at any time at the request of the subject. 
13.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, 
which requires the written approval by the sponsor.  The protocol amendment must be 
signed by the investigator and approved by the IRB before it may be implemented.  
Protocol amendments will be filed with the appropriate regulatory agency. 
13.9 Use of Information and Publication 
All information about the study drug, the sponsor’s operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by the sponsor or designee to the investigator and not previously published, is 
considered confidential and remains the sole property of the sponsor.  Case report forms 
also remain the property of the sponsor.  The investigator agrees to use this information 
for purposes of study execution through finalization and will not use it for other purposes 
without the written consent of the sponsor. 
The information developed in this study will be used by the sponsor in connection with 
the continued development of the study drug and thus may be disclosed as required to 
other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of the sponsor.  Publication or 
other public presentation of study drug data resulting from this study requires prior 
review and written approval of the sponsor.  Abstracts, manuscripts, and presentation 


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materials should be provided to the sponsor for review and approval at least 30 days prior 
to the relevant submission deadline.  Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, 
poster exhibition, or publication by the investigator until the sponsor has reviewed, 
commented on, and authorized such a presentation or manuscript for publication. 
14. FINAL CLINICAL STUDY REPORT 
The sponsor will retain ownership of the data from this study. 
The final CSR will be written within 1 year of completion of the clinical part of the study.  
This report will include a summary of the study results based on a statistical evaluation 
and clinical assessment of the protocol-defined endpoints. 
The final CSR will be submitted to the regulatory authorities. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents) and the 
1996 Version of the Declaration of Helsinki. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the 
investigator’s informed assent and consent documents, and related subject information 
and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, before any activity or procedure is undertaken 
that is not part of routine care. 
15.3 Approval by Institutional Review Board 
A valid IRB must review and approve this protocol before study initiation.  Written 
notification of approval is to be submitted by the investigator to the sponsor monitor 
before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature.  This written approval must consist 
of a completed sponsor IRB Approval Form or written documentation from the IRB 
containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval 
from the IRB, or a designee, must be received by the sponsor before implementation.  


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This written approval will consist of a completed IRB Approval form or written 
documentation from the IRB containing the same information. 


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16. REFERENCES 
 
1 
Andreassen TN, Klepstad P, Davies A, et al. Influences on the pharmacokinetics of oxycodone: a 
multicentre cross-sectional study in 439 adult cancer patients. Eur J Clin Pharmacol. 
2011;67:493-506. 
2 
Benziger DP, Kaiko RF, Miotto JB, Fitzmartin RD, Reder RF, Chasin M. Differential effects of 
food on the bioavailability of controlled-release oxycodone tablets and immediate-release 
oxycodone solution. J Pharm Sci. 1996;85:407-410. 
3 
Davis MP, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman R. Normal-release and 
controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support 
Care Cancer. 2003;11:84-92. 
4 
Foral PA, Ineck JR, Nystrom KK. Oxycodone accumulation in a hemodialysis patient. South Med 
J. 2007;100:212-214. 
5 
Gammaitoni AR, Davis MW. Comparison of the pharmacokinetics of oxycodone administered in 
three Percocet formulations. J Clin Pharmacol. 2002;42:192-197. 
6 
Grönlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Olkkola KT, Laine K. Exposure to oral 
oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by 
inhibition of CYP2D6 alone. Br J Clin Pharmacol. 2010;70:78-87. 
7 
Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and 
pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998;64:603-611. 
8 
Kapil R, Nolting A, Roy P, Fiske W, Benedek I, Abramowitz W. Pharmacokinetic properties of 
combination oxycodone plus racemic ibuprofen: two randomized, open-label, crossover studies in 
healthy adult volunteers. Clin Ther. 2004;26:2015-2025. 
9 
Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic 
patients undergoing renal transplantation. J Clin Anesth. 1996;8:13-18. 
10 
Kokubun H, Fukawa M, Matoba M, Hoka S, Yamada Y, Yago K. Pharmacokinetics and variation 
in the clearance of oxycodone and hydrocotarnine in patients with cancer pain. Biol Pharm Bull. 
2007;30:2173-2177. 
11 
Kummer O, Hammann F, Moser C, Schaller O, Drewe J, Krähenbühl S. Effect of the inhibition of 
CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin 
Pharmacol. 2011;67:63-71. 
12 
Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and 
pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active 
metabolites. Clin Pharmacol Ther. 2006;79:461-479. 
13 
Leow KP, Cramond T, Smith MT. Pharmacokinetics and pharmacodynamics of oxycodone when 
given intravenously and rectally to adult patients with cancer pain. Anesth Analg. 1995;80:296-
302. 
14 
Leow KP, Smith MT, Watt JA, Williams BE, Cramond T. Comparative oxycodone 
pharmacokinetics in humans after intravenous, oral, and rectal administration. Ther Drug Monit. 
1992;14:479-484. 
15 
Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother. 
2004;18:17-30. 


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11 July 2013 
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16 
Olesen AE, Upton R, Foster DJ, et al. A pharmacokinetic and pharmacodynamic study of oral 
oxycodone in a human experimental pain model of hyperalgesia. Clin Pharmacokinet. 
2010;49(:817-827. 
17 
Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of 
its use in the management of pain. Curr Med Res Opin. 2008;24:175-192. 
18 
Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the 
pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010;160:907-918. 
19 
Staahl C, Upton R, Foster DJ, et al. Pharmacokinetic-pharmacodynamic modeling of morphine 
and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. 
J Clin Pharmacol. 2008;48:619-631. 
20 
Pokela ML, Anttila E, Seppälä T, Olkkola KT. Marked variation in oxycodone pharmacokinetics 
in infants. Paediatr Anaesth. 2005;15:560-565. 
21 
El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 
6 months to 7 years old. J Clin Pharmacol. 2006;46:433-442. 
22 
Kalso E. Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative 
children. Br J Clin Pharmacol. 1995;39:214-215. 
23 
Kokki H, Rasanen I, Lasalmi M, et al. Comparison of oxycodone pharmacokinetics after buccal 
and sublingual administration in children. Clin Pharmacokinet. 2006;45:745-754. 
24 
Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanpera I. Pharmacokinetics of 
oxycodone after intravenous, buccal, intramuscular and gastric administration in children. Clin 
Pharmacokinet. 2004;43:613-622. 
25 
Olkkola KT, Hamunen K, Seppälä T, Maunuksela EL. Pharmacokinetics and ventilatory effects of 
intravenous oxycodone in postoperative children. Br J Clin Pharmacol. 1994;38:71-76. 
26 
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. Jan 1 2011;89(1):46-53. 
27 
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size 
when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2011. doi: 
10.1177/0091270011422812 
28 
Aleissa S, Parsons D, Grant J, Harder J, Howard J. Deep wound infection following pediatric 
scoliosis surgery: incidence and analysis of risk factors. Can J Surg. 2011;54:263-269. 
29 
Canavese F, Turcot K, De Rosa V, de Coulon G, Kaelin A. Cervical spine sagittal alignment 
variations following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. 
Eur Spine J. 2011;20:1141-1148. 
30 
Hwang SW, Samdani AF, Tantorski M, et al. Cervical sagittal plane decompensation after surgery 
for adolescent idiopathic scoliosis: an effect imparted by postoperative thoracic hypokyphosis. J 
Neurosurg Spine. 2011;15:491-496. 
31 
Ipp L, Flynn P, Blanco J, et al. The findings of preoperative cardiac screening studies in 
adolescent idiopathic scoliosis. J Pediatr Orthop. 2011;31:764-766. 
32 
Oto M, Shah SA, Mohammed MA, Rogers KJ, Yorgova P, Holmes L. Effectiveness and safety of 
posterior titanium instrumentation in children with adolescent idiopathic scoliosis: a prospective 
study. Eklem Hastalik Cerrahisi. 2011;22:124-128. 
33 
Charney RL, Yan Y, Schootman M, Kennedy RM, Luhmann JD. Oxycodone versus codeine for 
triage pain in children with suspected forearm fracture: a randomized controlled trial. Pediatr 
Emerg Care. 2008;24:595-600. 


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34 
Kokki H, Lintula H, Vanamo K, Heiskanen M, Eskelinen M. Oxycodone vs placebo in children 
with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of 
analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med. 2005;159:320-325. 
35 
Miner JR, Moore J, Gray RO, Skinner L, Biros MH. Oral versus intravenous opioid dosing for the 
initial treatment of acute musculoskeletal pain in the emergency department. Acad Emerg Med. 
2008;15:1234-1240. 
36 
Sharar SR, Carrougher GJ, Selzer K, O'Donnell F, Vavilala MS, Lee LA. A comparison of oral 
transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care 
Rehabil. 2002;23:27-31. 
37 
Malviya S, Merkel SI, Shayevitz JR, Voepel-Lewis T. The FLACC: a behavioral scale for scoring 
postoperative pain in young children. Pediatric Nursing. 1997;23(3):293-297. 
 


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Version:  v7.0 
 
 
 
17. ATTACHMENTS 
17.1 Schedule of Events 
Table 2: 
Schedule of Events 
 
 
 
 
STUDY PROCEDURES 
Screening 
(Day −14 to −1) 
OUTPATIENT 
HOSPITALIZATION 
 
 
End of 
Study/Early 
Discontinuationc 
Predose 
Check-in 
(Day −1) a,b 
Treatment 
(Day 1, 
Time Zero)b 
Informed consent/assent 
X 
 
 
 
Eligibility (inclusion/exclusion) 
X 
X 
 
 
Prior medication assessment 
X 
X 
 
 
Medical history 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
Temperature 
X 
 
X 
 
Pulse Oximetry 
 
 
X 
 
FLACC 
 
 
X 
 
Physical examinationd 
X 
 
 
 
Clinical laboratory testse 
X 
 
 
X 
Serum pregnancy test (females) 
X 
X 
 
 
Urine drug screenf 
X 
 
 
 
Safety electrocardiogram 
X or 
X 
 
 
Study drug administration 
 
 
X 
 
Pharmacokinetic sampling 
 
 
X 
 
Adverse event assessment 
 
 
Xg 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
a 
The predose check-in (Day −1) can be performed the same day as surgery (Day 1).  At the predose 
check-in, eligibility and prior medications will be reviewed and updated as needed.  Medical history 
will be recorded if it was not completed at Screening. 
b 
Day −1 and Day 1 are adjacent and not separated by a Day 0. 
c 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 24 hours after dosing 
with Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do so, 
subjects will be discharged from the study.  
d 
The physical examination will include measurements of height, weight, and body mass index. 
e 
Complete blood count with differential and clinical chemistry will be performed at Screening and End 
of Study/Early Discontinuation.  Urinalysis will be performed at Screening only. 
f 
The urine drug screen will test for drugs of abuse (amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, phencyclidine, and benzodiazepines) and alcohol (not required for subjects less 
than 2 years of age). 


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g 
During the study, subjects will be asked about adverse events.  If an adverse event occurs, clinic staff 
may advise the subject to remain at the hospital until a decision is made that it is safe for the subject to 
be discharged. 


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17.2 Treatment Day Procedures 
Table 3: 
Treatment Day Procedures 
Time, related to 1st dose of 
Oxycodone Oral Solution 
Pre-
dose 
0 min 
5 min 
10 min 
15 min 
30  min 
45 min 
60 min 
1 hr   
15 min 
1 hr   
30 min 
1 hr   
45 min 
2 hr 
2 hr   
15 min 
2 hr   
30 min 
2 hr   
45 min 
Vital signs (BP, HR, Resp.) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pulse oximetrya 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (Under age 2) 
Xb 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (2 to <17) 
Xb 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
Study drug administrationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FLACCd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time, related to 1st dose of 
Oxycodone Oral Solution 
3 hr 
3 hr   
15 min 
3 hr   
30 min 
3 hr   
45 min 
4 hr 
6 hr 
8 hr 
10 hr 
12 hr 
14 hr 
16 hr 
18 hr 
20 hr 
22 hr 
24 hr 
Vital signs (BP, HR, Resp.)a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrya 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
PK sampling (Under age 2) 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
PK sampling (2 to <17) 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
X 
Study drug administrationc 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
FLACCd 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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a Pulse oximetry will begin as soon as possible following the procedure and will continue until 8 hours after the last study dose.  The following timepoints will be captured in the CRF: 5, 10, 30 and 60 
minutes, 2 hours, then every 2 hours until 8 hours after the last dose of Oxycodone Oral Solution. 
b Blood samples for pharmacokinetic assessment will be collected at the predose time point (within 15 minutes of dosing);  
c The study drug will be administered after the surgery when subjects have been postoperatively cleared to transition to oral pain medication in place of the standard analgesic medication.  If pain control 
is inadequate with study drug, the investigator may administer rescue medication for breakthrough pain after dosing. 
d The FLACC will also be administered prior to the subject receiving each rescue dose of Fentanyl. 
e AEs and Con Meds will be monitored throughout the course of the study. 
 
 
 


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17.3 Investigator’s Agreement 
 
PROTOCOL NUMBER: 
2012O004 
PROTOCOL TITLE: 
A PHASE IV STUDY TO EVALUATE THE SAFETY 
AND PHARMACOKINETICS OF OXYCODONE 
ORAL SOLUTION IN PEDIATRIC AND 
ADOLESCENT SUBJECTS 
FINAL PROTOCOL: 
AMENDMENT #1; 11 July 2013 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein.  I will 
ensure that all subinvestigators and other study staff members have read and understand 
all aspects of this protocol.  I agree to cooperate fully with VistaPharm, Inc. and Lehigh 
Technologies, Inc., or designee during the study.  I will adhere to all FDA, ICH, and 
other applicable regulations and guidelines regarding clinical trials on an investigational 
product during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 


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17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) 
 
Categories 
Scoring 
 
0 
1 
2 
Face 
No particular 
expression or smile 
Occasional grimace 
or frown, withdrawn, 
disinterested 
Frequent to constant 
quivering chin, 
clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, 
tense 
Kicking, or legs 
drawn up 
Activity 
Lying quietly, 
normal position, 
moves easily 
Squirming, shifting 
back and forth, tense 
Arched, rigid or 
jerking 
Cry 
No cry, (awake or 
asleep) 
Moans or whimpers; 
occasional complaint 
Crying steadily, 
screams or sob, 
frequent complaints 
Consolability 
Content, relaxed 
Reassured by 
occasional touching, 
hugging or being 
talked to, distractible 
Difficult to console 
or comfort 
 


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18. APPENDICES 
A. Address List 
B. OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved Label 
and Full Prescribing Information 


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A. 
Address List 
18.1.1 
Sponsors 
Name: 
VistaPharm, Inc. 
Address: 
7256 Ulmerton Road 
 
Largo, FL 33771 
Phone: 
(727) 530-1633 
Fax: 
(727) 531-5427 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
Name: 
Lehigh Valley Technologies, Inc. 
Address: 
514 North 12th Street 
 
Allentown, PA 18102 
Phone: 
(610) 782-9780 
 
 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
18.1.2 
Clinical Research Organization 
Name: 
Cognitive Research Corporation 
Address: 
200 Central Avenue, Suite 1230 
 
Saint Petersburg, FL 33703 
Phone: 
(727) 897-9000 
Fax: 
(727) 897-9009 
Project Manager: 
Eva M. Kemper, MSHS 
Director, Clinical Projects 
 
 


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B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information 
 


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18 Sept 2013 
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A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY 
OF OXYCODONE ORAL SOLUTION IN PEDIATRIC AND ADOLESCENT 
SUBJECTS 
 
PROTOCOL DATE: 
Version 7.1, Final 25 April 2013 
Amendment #1, 11 July 2013 
Amendment #2, 18 September 2013 
 
SPONSORED BY: 
VistaPharm, Inc. 
7256 Ulmerton Road 
Largo, FL 33771 
Phone:  (727) 530-1633 
 
 
Lehigh Valley Technologies, Inc. 
514 North 12th Street 
Allentown, PA 18102 
Phone:  (610) 782-9780 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
Cognitive Research Corporation
200 Central Avenue, Suite 1230 
St. Petersburg, FL 33701 
Phone: (727) 897-9000 
Fax: (727) 897-9009 
 
This study will be performed in compliance with Good Clinical Practices and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to 
the extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, 
or as required by law.  Persons to whom this information is disclosed should be informed that this 
information is confidential and may not be further disclosed without the express permission of 
VistaPharm, Inc. 
 


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1. PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Sponsor Contact Information 
Role in Study 
Name 
Address and  
Telephone Number 
Clinical Study Leader 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
Clinical Operations Leader 
Eva M. Kemper, 
MSHS 
Director, Clinical 
Projects  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-690-2667 
Physician 
Lawrence Blob, M.D.  
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 410-262-1908 
24-hour Emergency Contact 
Thomas J. Hochadel, 
Pharm.D. 
Chief Operating 
Officer 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 727-515-1334 
 
Secondary Contact: 
Deborah Lees, R.N.  
Assistant Project 
Manager 
 
Company Name: CRC 
Address: 200 Central Ave,  
Suite 1230 
Saint Petersburg, FL 33701  
Telephone: 727-897-9000 
Cell: 813-943-8249 
 


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2. SYNOPSIS 
 
PRODUCT NAME 
OXYCODONE ORAL SOLUTION 
PROTOCOL NUMBER 
2012O004 
DEVELOPMENT PHASE 
PHASE IV 
PROTOCOL TITLE 
A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS 
AND SAFETY OF OXYCODONE ORAL SOLUTION IN PEDIATRIC 
AND ADOLESCENT SUBJECTS 
INDICATION 
Moderate to severe pain 
PRINCIPAL 
INVESTIGATOR 
This is a multicenter study.  The lead Principal Investigator will be: 
Senthilkumar Sadhasivam, M.D. 
Cincinnati Children’s Hospital Medical Center 
3333Burnet Avenue, MLC2001 
Cincinnati, OH 45229 
PLANNED STUDY 
SITES 
Up to 10 sites in the US. 
 
OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to 
evaluate the safety of single and multiple doses of Oxycodone Oral 
Solution in pediatric and adolescent subjects for postoperative pain.   
STUDY DESIGN 
This is a Phase IV study to characterize the pharmacokinetics and to 
evaluate the safety of Oxycodone Oral Solution administered to pediatric 
and adolescent subjects for postoperative pain.  It is an open-label, 
multicenter study conducted at up to 10 sites.  Subjects may be enrolled 
preoperatively, up to 14 days before surgery, or postoperatively with the 
expectation that they will require intravenous (IV) access after the surgery 
and postoperative analgesia with an opiate-level medication.  After dosing 
with Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 to <17, and a dose to be 
determined based on pharmacokinetic (PK) modeling from the interim 
analyses for subjects under age 2), subjects will be carefully monitored for 
safety.  A total of 110 pediatric and adolescent male or female subjects will 
be enrolled, including a minimum of 20 subjects under age 2 (5 subjects 
ages 0 to <2 months, 5 subjects ages 2 to <6 months, and 10 subjects ages 6 
months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 
13 to <17 years.  Subjects within each age group will be evenly distributed 
by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 
to 12 years and 10 ages 13 to <17 years have completed the study.  The 
interim analysis will include PK, pulse oximetry readings, vital sign 
measurements, adverse events (AEs) and concomitant medications.  The 
dose of Oxycodone Oral Solution that the subjects ages 6 months to <2 
years will receive will be based on an evaluation of the safety and PK 
observed from this interim analysis. 
An additional interim analysis will be run after at least half of the subjects 
aged 6 months to <2 years have completed the study.  The interim analysis 
will include PK, pulse oximetry readings, vital sign measurements, AEs 


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and concomitant medications.  The dose of Oxycodone Oral Solution that 
the subjects ages 0 to <2 months and 2 months to <6 months will receive 
will be based on an evaluation of the safety and PK observed from this 
interim analysis. 
The study will consist of a Screening period (preoperatively, up to 14 days 
before surgery, or postoperatively); a predose check-in (Predose); a 
treatment period after surgery (Day 1, Time Zero); and an End-of-Study 
assessment.  The total duration of the study, excluding Screening, will be 
approximately 1 full day. 
Eligible subjects who provide assent (according to local standard of care or 
IRB directive) and whose parent(s) or legal guardian(s) provide consent as 
required will have study assessments performed at Screening.  Following 
surgery, subjects will receive standard care, including parenteral analgesia 
with a nonoxycodone, nonoxymorphone medication that will not interfere 
with the measurement or metabolism of oxycodone.  At this time (Predose), 
they will have a predose check-in to have eligibility confirmed.   
After subjects ages 2 to <17 have been postoperatively cleared to transition 
to oral pain medication, Oxycodone Oral Solution will be administered at 
Time Zero of Day 1 in place of the standard analgesic medication.  The first 
10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, who will 
be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  If pain control is inadequate with Oxycodone 
Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) 
every 4 hours as rescue medication for breakthrough pain after dosing.  Use 
of other rescue pain medication is permissible in accordance with hospital 
pain management guidelines or facilities standard of care.  Any rescue 
medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to 
oral pain medication, they will receive a single dose of Oxycodone Oral 
Solution at Time Zero of Day 1 in place of the standard analgesic 
medication.  The dose will be determined based on PK modeling from the 
interim analyses.  If pain control is inadequate with Oxycodone Oral 
Solution, as indicated by a score of moderate to severe (4-10) on the 
FLACC, the subject will be given Fentanyl via Nurse-Controlled Analgesia 
(NCA).  Use of other rescue pain medication is permissible in accordance 
with hospital pain management guidelines or facilities standard of care.  
Any rescue medications used will be provided by the study site pharmacy.. 
Subjects will undergo an End-of-Study assessment at least 24 hours after 
receiving the first dose of Oxycodone Oral Solution.  At that time, if the 
study staff determines that it is safe to do so, subjects will be discharged 
from the study. 
Safety will be assessed by monitoring AEs, clinical laboratory test results, 
vital sign measurements, temperature, pulse oximetry, and physical 
examination findings. 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) will be 
used to measure pain prior to and 20, 40, 60, 90, 120, 180, and 240 minutes 
after the dose of Oxycodone Oral Solution in subjects under age 2.  The 
FLACC will also be administered prior to the subject receiving each dose 
of Fentanyl or other rescue pain medication. 


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Serial blood samples for PK analysis will be collected for the determination 
of plasma concentrations of oxycodone and its metabolites (noroxycodone, 
oxymorphone and noroxymorphone).  For subjects 2 years old and above, 
samples will be collected prior to the first dose (within 15 minutes of 
dosing); 30 (between 25-35 min), and 60 (between 50-70 min) minutes 
after dosing; and 2 (between 110-130 min), 4 (between 3-5 hrs), 6 (between 
4-7 hrs), 8 (between 6-10 hrs), 12 (between 12-18 hrs), and 24 (between 
22-24 hrs) hours after the first dose of Oxycodone Oral Solution. For 
subjects under age 2, serial blood samples for PK analysis will be collected 
prior to the first dose (within 15 minutes of dosing); 30 (between 25-35 
min), and 60 (between 50-70 min) minutes after dosing; and 2 (between 
110-130 min), 6 (between 4-7 hrs), 12 (between 12-18 hrs), and 24 
(between 22-24 hrs) hours after dosing. 
PLANNED NUMBER OF 
SUBJECTS 
A total of 110 subjects, including a minimum of 20 subjects under age 2, 30 
ages 2 to 6 years, 30 ages 7 to 12 years and 30 ages 13 to <17 years, are 
planned for this study to ensure adequate evaluation of the safety and PK 
profiles of Oxycodone Oral Solution. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria  
A subject will be eligible for inclusion in the study if he or she meets the 
following criteria: 
1. Is male or female <17 years of age at the time of dosing. 
2. Subject 2 to <17 years of age, be in at least the 25% for weight 
according to the Center for Disease Control pediatric growth charts 
and weighs at least 28 lb at the time of dosing with study drug. 
3. Is generally healthy defined as American Society of Anesthesiologists 
(ASA) Physical Status classification grade I or II (except for the 
condition for which the procedure is being performed), documented 
by medical history; physical examination (including, but not limited 
to, the cardiovascular, gastrointestinal, respiratory, and central 
nervous systems); vital sign assessments; electrocardiogram; clinical 
laboratory assessments; and general observations.   
4. Has a negative urine pregnancy test predose (for females of 
childbearing potential). 
5. Is an outpatient prior to admission for a surgical procedure and is 
expected to remain hospitalized for at least 24 hours after dosing with 
study drug. 
6. Is anticipated to have postsurgical pain requiring a parenteral 
analgesic regimen using a short-acting opioid analgesic and is 
anticipated to be switched to an oral opioid for at least 1 dose 
(according to institution standard of care). 
7. Has an indwelling access catheter for blood sampling. 
8. Agrees to comply with all protocol requirements.  If not old enough, 
the legally responsible parent(s) or legal guardian(s) must agree to 
comply with all protocol requirements. 
9. Has been informed of the nature of the study and informed consent 
and assent (as appropriate) have been obtained from the legally 
responsible parent(s) or legal guardian(s) and the subject, 
respectively, in accordance with institutional review board 
requirements. 


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Exclusion criteria  
A subject will be excluded from the study if he or she meets the following 
criteria: 
1. Has the presence or history of a clinically significant disorder 
involving the cardiovascular, respiratory, renal, gastrointestinal, 
immunologic, hematologic, endocrine, or neurologic system(s) or 
psychiatric disease (except for the condition for which the procedure 
is being performed) greater than grade II on ASA Physical Status 
classification as determined by the clinical investigator. 
2. Has any clinical laboratory test result documented as “alert”, “critical” 
or “panic” per institution laboratory ranges or has aspartate 
transaminase, alanine transaminase, or alkaline phosphatase > 2.0 x 
the upper limit of normal (ULN); total bilirubin > 1.5 x the ULN; 
serum creatinine > 1.5 x the ULN; or blood urea nitrogen > 1.5 x the 
ULN. 
3. Had a clinically significant illness (ASA Physical Status classification 
>II), except for the condition for which the procedure is being 
performed, in the 28 days before dosing with study drug as 
determined by the clinical investigator. 
4. Is a lactating or breastfeeding female. 
5. Uses any medication known to be an inhibitor or inducer of CYP3A4 
within 14 days (for inhibitors such as the azole-antifungal agents 
voriconazole and ketoconazole, macrolide antibiotics such as 
erythromycin, and protease inhibitors such as ritonavir) or 28 days 
(for inducers such as rifampin, carbamazepine, and phenytoin) of 
dosing with study drug. Use of any monoamine oxidase inhibitor or 
St. John’s wort is prohibited from 28 days before dosing until 14 days 
after dosing.  Standard daily dose multivitamins (nontherapeutic 
doses) may be taken until enrollment into the study but will be 
restricted during the study. 
6. Consumes alcohol- or xanthine-containing products within 8 hours 
before dosing and during periods when blood samples are collected. 
7. Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-
containing products within 5 days of dosing.  Fruit juices, with the 
exception of apple and grape, will be prohibited during the study. 
8. Is a smoker or has used nicotine or nicotine-containing products 
within 30 days of dosing. 
9. Has a history of alcohol or drug addiction or abuse within the last 
year. 
10. Temperature >100°F at time of initial administration of study 
medication. 
 
11. Donated blood within 28 days or plasma within 14 days of dosing or 
plans to donate them within 4 weeks after completing the study. 
12. Has a history of relevant drug allergies, food allergies, or both 
(i.e., allergy to oxycodone, allergy to related drugs, or any significant 
food allergy that could interfere with the study). 
13. Is intolerant to direct venipuncture. 
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15. Has taken oxycodone or oxymorphone within the 48 hours before 
anticipated dosing with study drug. 
16. Is not suitable for entry into the study in the opinion of the 
investigator. 
INVESTIGATIONAL 
PRODUCT 
Oxycodone Oral Solution provided by VistaPharm, Inc., supplied in 
500-mL bottles.  Oxycodone Oral Solution contains 4.5 mg of oxycodone 
free base per 5 mL (5 mg oxycodone HCl/5 ml) and the following inactive 
ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid anhydrous 
US Pharmacopeia (USP), glycerin natural USP, sorbitol solution 70% USP, 
FD&C Red #40 , raspberry flavor, and water. 
TREATMENT REGIMEN 
Each subject in the 2 to 6, 7 to 12 and 13 to <17 age groups will receive a 
dose of Oxycodone Oral Solution (0.1 mg/kg for children ages 2 to 6, 0.08 
mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to <17) in place of the 
standard analgesic dose after being postoperatively cleared to transition to 
oral pain medication.  The first 10 subjects in each of these age groups, 
who will be included in the first interim analysis, will only receive 1 dose 
of Oxycodone Oral Solution.  Subjects in these age groups enrolled in the 
study after the interim analysis is completed may receive additional doses 
every 4-6 hours as needed.  Each subject under age 2 will receive a single 
dose of Oxycodone Oral Solution.  The dose will be determined based on 
PK modeling from the interim analyses.  Oxycodone Oral Solution will be 
administered with an oral medication syringe. 
CRITERIA FOR 
EVALUATION 
Pharmacokinetic endpoints: 
• 
Area under the plasma concentration versus time curve from 
Time Zero to the last measurable concentration (AUC0-t) 
• 
Area under the plasma concentration versus time curve from 
Time Zero to infinity (AUC0-inf) 
• 
Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• 
Maximum measured plasma concentration (Cmax) 
• 
Time of the maximum measured plasma concentration (Tmax) 
• 
Apparent first-order terminal elimination rate constant (Kel) 
• 
Apparent first-order terminal elimination half-life (t1/2) 
• 
Apparent clearance (CL/F) 
• 
Volume of distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
Safety endpoints: 
Safety will be assessed by the monitoring and recording of AEs; clinical 
laboratory results (including hematology, serum chemistry, and urinalysis); 
vital sign measurements (systolic and diastolic blood pressures, heart rate, 
and respiratory rate); temperature; pulse oximetry; and physical 
examination findings. 
 Exploratory Study Endpoints: 
Analgesic sparing will be the surrogate efficacy endpoint in children under 
age 2.The Total FLACC Score will be an exploratory endpoint in children 
under age 2. 
 


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STATISTICAL 
METHODS 
Analysis Populations 
PK Population: the PK population will consist of all subjects who receive 
study drug and have at least 1 measureable plasma concentration. 
PK Parameter Population: all subjects who receive study drug and for 
which at least one PK parameter can be determined. 
Safety Population: the safety population will consist of all subjects who 
receive study drug. 
Subject Characteristics and Disposition 
For categorical variables, frequencies and percentages will be presented.  
Continuous variables will be summarized using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized.  The 
number of subjects who enroll in the study and the number and percentage 
of subjects who complete the study will be presented.  The frequency and 
percentage of subjects who withdraw or discontinue from the study, along 
with the reason for withdrawal or discontinuation, will also be summarized. 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and 
noroxymorphone) plasma concentrations will be listed and summarized.  
Each subject’s oxycodone plasma concentrations will be graphed by using 
both a normal scale y-axis and a logarithmic scale y-axis.  Mean oxycodone 
plasma concentrations for each age group will also be graphed using 
scheduled elapsed sampling times for both the normal and logarithmic scale 
y-axis. 
Pharmacokinetic parameters will be listed for each subject and summarized 
by group.  Key PK parameters will be contrasted with adult values from the 
literature. 
Other PK analyses may be performed as appropriate. 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities 
and will be summarized overall.  Adverse events will also be summarized 
by severity and relationship to study drug.  Serious AEs and AEs leading to 
discontinuation of study drug will also be summarized. 
Actual values and changes from Baseline for clinical laboratory results, 
pulse oximetry, and vital sign measurements will be summarized at each 
time point using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) or shift tables where appropriate.  Physical 
examination findings will be presented in a listing. 
  
SAMPLE SIZE 
DETERMINATION 
The evaluable sample size for this study is powered to target a 
95% confidence interval within 60% and 140% of the geometric mean 
estimates of clearance and volume of distribution for oxycodone with at 
least 80% power. 
Because of an anticipated dropout rate of 33%, a recruited sample size of 
30 subjects is considered sufficient to ensure 20 evaluable subjects to assess 
the PK profiles of Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, 


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the trial will enroll 110 subjects to gather adequate safety information in
the pediatric/adolescent patient population. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods will be as 
follows: 
Screening is up to 14 days. 
The total study duration for each subject is approximately 1 full day, 
excluding Screening. 
The maximum treatment duration for each subject is 1 full day. 


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3. TABLE OF CONTENTS 
 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ...........................................................................................10 
3.1 
List of Tables .....................................................................................................13 
4. 
LIST OF ABBREVIATIONS.....................................................................................14 
5. 
INTRODUCTION ......................................................................................................16 
5.1 
Background and Rationale ................................................................................16 
5.1.1 Indication and Usage .............................................................................16 
5.1.2 Description ............................................................................................16 
5.1.3 Pharmacodynamics ................................................................................17 
5.1.4 Pharmacokinetics ...................................................................................17 
5.1.4.1 
Absorption .................................................................................17 
5.1.4.2 
Distribution ...............................................................................17 
5.1.4.3 
Metabolism ................................................................................18 
5.1.4.4 
Elimination ................................................................................18 
5.1.5 Clinical Experience ...............................................................................18 
5.1.6 Study Rationale .....................................................................................18 
5.2 
Summary of Potential Risks and Benefits .........................................................18 
5.2.1 Potential Risks .......................................................................................18 
5.2.2 Benefits ..................................................................................................19 
6. 
OBJECTIVE ...............................................................................................................20 
7. 
STUDY DESIGN .......................................................................................................20 
7.1 
Overall Study Design and Plan .........................................................................20 
7.2 
Discussion of Study Design ..............................................................................22 
7.3 
Study Sites .........................................................................................................22 
7.4 
Point of Contact .................................................................................................22 
8. 
SUBJECT POPULATION .........................................................................................22 
8.1 
Selection of Study Population ...........................................................................22 
8.1.1 Inclusion Criteria ...................................................................................22 
8.1.2 Exclusion Criteria ..................................................................................23 
8.2 
Removal of Subjects from Therapy or Assessment ..........................................24 
9. 
STUDY TREATMENTS............................................................................................25 
9.1 
Method of Assigning Subjects to Treatment Groups ........................................25 


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9.1.1 Under Age 2 ..........................................................................................25 
9.1.2 Ages 2 to <17 ........................................................................................25 
9.2 
Identification of Investigational Products .........................................................25 
9.3 
Treatment Administered ....................................................................................25 
9.3.1 Under Age 2 ..........................................................................................25 
9.3.2 Ages 2 to <17 ........................................................................................25 
9.4 
Storage ...............................................................................................................26 
9.5 
Labeling .............................................................................................................26 
9.6 
Drug Accountability ..........................................................................................26 
9.7 
Blinding and Unblinding Treatment Assignment .............................................26 
9.8 
Selection of Dose in the Study ..........................................................................26 
9.9 
Selection of Timing of Dose for Each Subject ..................................................27 
9.10 Treatment Compliance ......................................................................................27 
9.11 Permitted and Prohibited Therapies ..................................................................27 
9.11.1 Permitted Therapies ...............................................................................27 
9.11.2 Prohibited Therapies ..............................................................................28 
9.12 Rescue Medication ............................................................................................28 
10. STUDY PROCEDURES ............................................................................................29 
10.1 Screening (Day −14 to Day 1) ...........................................................................29 
10.2 Predose Check-in (Predose) ..............................................................................29 
10.3 Open-Label Treatment (Day 1, After Surgery) .................................................29 
10.4 End-of-Study/Early Discontinuation .................................................................31 
11. STUDY ASSESSMENTS ..........................................................................................32 
11.1 Pharmacokinetics ...............................................................................................32 
11.1.1 Sample Collection .................................................................................32 
11.1.2 Blood Volumes ......................................................................................33 
11.1.3 Sample Processing .................................................................................33 
11.1.4 Transport of Samples .............................................................................34 
11.1.5 Analytical Procedures ............................................................................34 
11.1.5.1 Bioanalytical Sample Analyses .................................................34 
11.1.5.2 Bioanalytical Methodology .......................................................34 
11.2 Safety .................................................................................................................35 
11.2.1 Adverse Events ......................................................................................35 
11.2.1.1 Adverse Event Definitions ........................................................35 
11.2.1.2 Eliciting and Documenting Adverse Events .............................36 
11.2.1.3 Reporting Adverse Events.........................................................36 


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11.2.1.4 Follow-up of Adverse Events....................................................39 
11.2.2 Laboratory Safety Assessments .............................................................40 
11.2.3 Vital Signs .............................................................................................40 
11.2.4 Pulse Oximetry ......................................................................................40 
11.2.5 Electrocardiogram .................................................................................40 
11.2.6 Physical Examination ............................................................................40 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) ..........................41 
12. STATISTICAL METHODS .......................................................................................41 
12.1 General Considerations .....................................................................................41 
12.2 Analysis Populations .........................................................................................41 
12.3 Statistical Analyses ............................................................................................41 
12.3.1 Subject Disposition and Demographic Characteristics .........................41 
12.3.2 Pharmacokinetic Analyses ....................................................................42 
12.3.3 Safety Analyses .....................................................................................42 
12.3.4 Exploratory Analyses ............................................................................42 
12.3.5 Interim Analyses ....................................................................................42 
12.4 Sample Size Determination ...............................................................................43 
13. STUDY CONDUCT ...................................................................................................43 
13.1 Sponsor and Investigator Responsibilities ........................................................43 
13.1.1 Sponsor Responsibilities .......................................................................43 
13.1.2 Investigator Responsibilities .................................................................43 
13.2 Site Initiation .....................................................................................................44 
13.3 Screen Failures ..................................................................................................45 
13.4 Study Documents ..............................................................................................45 
13.4.1 Good Clinical Practice Documents .......................................................45 
13.4.2 Case Report Forms ................................................................................45 
13.4.3 Source Documents .................................................................................46 
13.5 Data Quality Control .........................................................................................46 
13.5.1 Monitoring Procedures ..........................................................................46 
13.5.2 Data Management ..................................................................................47 
13.5.3 Quality Assurance/Audit .......................................................................47 
13.6 Study Termination .............................................................................................48 
13.6.1 Regular Study Termination ...................................................................48 
13.6.2 Premature Study Termination ...............................................................48 
13.7 Study Site Closure .............................................................................................48 
13.7.1 Record Retention ...................................................................................48 


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13.7.2 Sample Retention ..................................................................................49 
13.8 Changes to the Protocol .....................................................................................49 
13.9 Use of Information and Publication ..................................................................49 
14. FINAL CLINICAL STUDY REPORT ......................................................................50 
15. ETHICAL AND LEGAL CONSIDERATIONS ........................................................50 
15.1 Declaration of Helsinki and Good Clinical Practice .........................................50 
15.2 Subject Information and Informed Consent ......................................................50 
15.3 Approval by Institutional Review Board ...........................................................50 
16. REFERENCES ...........................................................................................................52 
17. ATTACHMENTS .......................................................................................................55 
17.1 Schedule of Events ............................................................................................55 
17.2 Treatment Day Procedures ................................................................................56 
17.3 Investigator’s Agreement ..................................................................................58 
17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) ...............................59 
18. APPENDICES ............................................................................................................60 
A. 
Address List .......................................................................................................61 
18.1.1 Sponsors ................................................................................................61 
18.1.2 Clinical Research Organization .............................................................61 
B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information ............................................................62 
 
3.1 
List of Tables 
Table 1: 
Sponsor Contact Information ..................................................................2 
Table 2: 
Schedule of Events ................................................................................55 
Table 3: 
Treatment Day Procedures ....................................................................56 


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4. LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve 
AUC0-inf 
Area under the concentration-time curve from Time Zero to infinity 
AUC0-t 
Area under the concentration-time curve from Time Zero to the last 
measurable concentration 
Cmax  
Observed maximum plasma concentration 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG  
Electrocardiogram 
EDC 
Electronic data capture 
FDA  
Food and Drug Administration 
FLACC 
Face, Legs, Activity, Cry, Consolability Scale 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonisation 
IRB  
Institutional review board 
ITT 
Intention-to-Treat Population 
IV 
Intravenous 
Kel 
Elimination rate constant  
kg 
Kilogram 
L 
Liter 
lbs 
Pounds 
mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
NCA 
Nurse-Controlled Analgesia 
PK 
Pharmacokinetic 
RPM 
Revolutions per minute 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 


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SOC 
Standard of care 
t1/2 
Apparent elimination half-life 
TBV 
Total blood volume 
Tmax 
Time of maximum concentration 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
 


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5. INTRODUCTION 
5.1 
Background and Rationale 
5.1.1 
Indication and Usage 
Oxycodone (4, 5α-epoxy-14-hydroxy-3-methoxy-17methylmorphinan-6-one 
hydrochloride) is a semisynthetic opioid that has been in clinical use since 1917 and 
approved for use in the US since 1950.  Developed by VistaPharm, Inc., oxycodone 
hydrochloride (HCl) US Pharmacopeia (USP) oral solution, 5 mg per 5 mL, is an 
immediate-release oral formulation of oxycodone hydrochloride indicated for the 
management of moderate to severe acute and chronic pain where the use of an opioid 
analgesic is appropriate.  This product was approved by the Food and Drug 
Administration (FDA) on January 12, 2012 (application New Drug Application 201194).  
In addition, Lehigh Valley Technologies, Inc. has developed Oxycodone Hydrochloride 
Oral Solution available as a 100 mg/5 mL (20 mg/mL) concentration which is indicated 
for use in opioid-tolerant patients only. This product was approved by the Food and Drug 
Administration (FDA) on October 20, 2010 (application New Drug Application 200535). 
The results of the study described with the current protocol will be utilized to meet 
regulatory requirements for both VistaPharm, Inc. and Lehigh Valley Technologies, Inc.    
Oxycodone HCl is currently available in the US in a number of other forms and 
combinations.  Oxycodone is a Schedule II controlled substance. The VistaPharm, Inc., 
oxycodone hydrochloride (HCl) (USP) oral solution, 5 mg per 5 mL, will be utilized for 
the purposes of this protocol. 
5.1.2 
Description 
Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium 
alkaloid thebaine.  Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is 
considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). 
Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-
17methylmorphinan-6-one hydrochloride and has the following structural formula: 
 


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5.1.3 
Pharmacodynamics 
Oxycodone is a semisynthetic narcotic with multiple actions qualitatively similar to those 
of morphine; the most prominent of these involve the central nervous system and organs 
composed of smooth muscle.  The principal actions of therapeutic value of oxycodone are 
analgesia and sedation. 
Oxycodone is similar to codeine and methadone in that it retains at least one-half of its 
analgesic activity when administered orally. 
Additional detailed information on the pharmacodynamic properties of oxycodone 
hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the Approved Label 
and Full Prescribing Information (Appendix B). 
5.1.4 
Pharmacokinetics 
5.1.4.1 Absorption 
About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in 
comparison with a parenteral dose.  This high oral bioavailability (compared to other oral 
opioids) is due to lower presystemic metabolism, first-pass metabolism, or both of 
oxycodone. 
A single-dose food effect study was conducted in normal adult volunteers using the 
5 mg/5 mL solution.  The concurrent intake of a high fat meal was shown to enhance the 
extent (a 27% increase in the area under the plasma concentration versus time curve 
[AUC]) but not the rate of oxycodone absorption from the oral solution.  In addition, food 
caused a delay in the time of maximum concentration (Tmax) (1.25 to 2.54 hours). 
5.1.4.2 Distribution 
Following intravenous (IV) administration, the volume of distribution for oxycodone was 
2.6 L/kg.  Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%.  
Oxycodone has been found in breast milk. 


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5.1.4.3 Metabolism 
Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, 
and their glucuronides.  The major circulating metabolite is noroxycodone with an AUC 
ratio of 0.6 relative to that of oxycodone.  Oxymorphone is present in the plasma only in 
low concentrations.  The analgesic activity profile of other metabolites is not known at 
present. 
The formation of oxymorphone but not noroxycodone is mediated by CYP2D6 and as 
such its formation can, in theory, be affected by other drugs. 
5.1.4.4 Elimination 
Oxycodone and its metabolites are excreted primarily via the kidney.  The amounts 
measured in the urine have been reported as follows:  up to 19% was reported for free 
oxycodone; up to 50% was reported for conjugated oxycodone; 0% was reported for free 
oxymorphone; no greater than 14% was reported for conjugated oxymorphone; and both 
free and conjugated noroxycodone have been found in the urine but not quantified.  The 
total plasma clearance was 0.8 L/min for adults. 
Additional detailed information on the physical, chemical, and pharmaceutical properties 
of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, can be found in the 
Approved Label and Full Prescribing Information (Appendix B). 
5.1.5 
Clinical Experience 
Oxycodone hydrochloride USP oral solution has been studied in adult populations, with a 
focus on pharmacokinetics, safety, and tolerability.  A total of 4 clinical pharmacokinetic 
(PK) and bioavailability studies have been conducted to support the development and 
labeling of oxycodone hydrochloride USP oral solution. 
In addition, there are a number of published studies in the medical literature that report on 
the pharmacokinetics of oxycodone in clinical and nonclinical settings, in a variety of 
doses and routes of administration.1-19 
5.1.6 
Study Rationale 
Despite published studies on dosing and pharmacokinetics in pediatric populations,20-25 
oxycodone has never received an official indication for use in children.  Pursuant to the 
Pediatric Research Equity Act (21 USC 355c), the FDA has requested that VistaPharm, 
Inc. and Lehigh Valley Technologies, Inc. conduct a postapproval and postmarketing 
(Phase IV) PK and safety study in subjects < 17 years of age. 
5.2 
Summary of Potential Risks and Benefits 
5.2.1 
Potential Risks 
The most frequently observed adverse events (AEs) reported with oxycodone include 
light headedness, dizziness, sedation, nausea, and vomiting.  These effects seem to be 
more prominent in subjects who can walk than in subjects who cannot walk, and some of 


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these adverse reactions may be alleviated if the subject lies down.  Other AEs include 
euphoria, dysphoria, constipation, skin rash, and pruritus. 
Additional detailed information on potential AEs and on specific warnings and 
precautions with the use of oxycodone hydrochloride USP oral solution, 5 mg per 5 mL, 
can be found in the Approved Label and Full Prescribing Information (Appendix B). 
Given that some of the subjects will be infants and young children, the effect of multiple 
blood draws can be considered a potential risk or adverse situation.  A published review 
of the safe limits of blood sample volumes in child health research suggests that existing 
guidelines specify limits ranging from 1% to 5% of total blood volume (TBV) over 
24 hours.  However, the limited available evidence that includes findings from 
nonrandomized studies shows a minimal risk with one-off sampling of up to 5% of 
TBV.26 
For subjects 2 to <17 years of age, this protocol specifies a maximum of 9 serial blood 
samples of 0.5 mL each for a total of 4.5 mL, plus 2.5 mL each for standard clinical 
chemistry and hematology tests at Screening and End of Study.  In addition, up to 10 mL 
will be allotted as discard volume for the 9 PK samples and the final laboratory testing 
drawn through the indwelling catheter.  Existing blood draw guidelines for pediatric 
research suggest minimal risk is between 3% and 5% of total blood volume (TBV) over 
24 hours or on a single draw and TBV is generally estimated at 75-80 mL/kg.  For the 
smallest child permitted per protocol, in the 2 to <17 years of age group (weight: 28 lbs 
or 12.7 kg), the TBV would be estimated at 952.5 ml. The maximum safe volume drawn 
would therefore be between 28 and 47 mL, based on minimal risk at 3-5% TBV over 24 
hours.  The required 9.5 mL plus up to 10 mL of discard volume, or a cumulative volume 
of 19.5 mL, is well under the 3-5% of TBV guideline for the smallest eligible participant 
using the smallest estimation of TBV. 26 
For the child less than 2 years of age, there is a maximum of 7 serial blood samples of 0.5 
mL each for a total of 3.5 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 8.5 mL is under the 3-5% 
of TBV guideline. 
5.2.2 
Benefits 
The size of the test dose (0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 
0.07 mg/kg for ages 13 to <17, and a dose to be determined based on PK modeling from 
the interim analyses for subjects under age 2) is designed to provide adequate analgesia 
for moderate to severe pain in substituting for the routinely prescribed postoperative pain 
regimen according to the custom of the attending physician and the institutional standard 
of care (SOC). 
No other benefit is anticipated or expected for subjects participating in this study. 


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6. OBJECTIVE 
The objective of this study is to characterize the pharmacokinetics and to evaluate the 
safety of single and multiple doses of Oxycodone Oral Solution in pediatric and 
adolescent subjects.   
7. STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a Phase IV study to characterize the pharmacokinetics and to evaluate the safety 
of Oxycodone Oral Solution administered to pediatric and adolescent subjects following 
a surgical procedure.  It is an open-label, multicenter study conducted at up to 10 sites.  
Subjects may be enrolled preoperatively, up to 14 days before surgery, or postoperatively 
with the expectation that they will require IV access after the surgery and postoperative 
analgesia with an opiate-level medication.  After dosing with Oxycodone Oral Solution 
(0.1 mg/kg for children ages 2 to 6, 0.08 mg/kg for ages 7 to 12, 0.07 mg/kg for ages 13 
to <17, and a dose to be determined based on PK modeling from the interim analyses for 
subjects under age 2), subjects will be carefully monitored for safety.  A total of 
110 pediatric and adolescent male or female subjects will be enrolled, including a 
minimum of 20 subjects under age 2 (5 subjects ages 0 to <2 months, 5 subjects ages 2 to 
<6 months, and 10 subjects ages 6 months to <2 years), 30 ages 2 to 6 years, 30 ages 7 to 
12 years and 30 ages 13 to <17 years.  Subjects within each age group will be evenly 
distributed by age and gender. 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects ages 6 
months to <2 years will receive will be based on an evaluation of the safety and PK 
observed from this interim analysis.  
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on an evaluation of the safety and PK observed from 
this interim analysis. 
The study will consist of a Screening period (preoperatively, up to 14 days before 
surgery, or postoperatively); a predose check-in (Predose); a treatment period after 
surgery (Day 1, Time Zero); and an End-of-Study assessment.  The total duration of the 
study, excluding Screening, will be approximately 1 full day. 
Eligible subjects who provide assent (according to local standard of care or IRB 
directive) and whose parent(s) or legal guardian(s) provide consent as required will have 
study assessments performed at Screening.  Following surgery, subjects will receive 
standard care, including parenteral analgesia with a nonoxycodone, nonoxymorphone 


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medication that will not interfere with the measurement or metabolism of oxycodone.  At 
this time (Predose), they will have a predose check-in to have eligibility confirmed.   
After subjects ages 2 to <17 years have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of Day 1 in 
place of the standard analgesic medication.  The first 10 subjects in each of the 2 to 6, 7 
to 12 and 13 to <17 age groups, who will be included in the first interim analysis, will 
only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age groups enrolled in 
the study after the interim analysis is completed may receive additional doses every 4-6 
hours as needed.  If pain control is inadequate with Oxycodone Oral Solution, the 
investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 6 hours or an IV 
dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue medication for 
breakthrough pain after dosing.  Use of other rescue pain medication is permissible in 
accordance with hospital pain management guidelines or facilities standard of care.  Any 
rescue medications used will be provided by the study site pharmacy. 
After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero of 
Day 1 in place of the standard analgesic medication.  The dose will be determined based 
on PK modeling from the interim analyses.  If pain control is inadequate with Oxycodone 
Oral Solution, as indicated by a score of moderate to severe (4-10) on the FLACC, the 
subject will be given Fentanyl via NCA.  Use of other rescue pain medication is 
permissible in accordance with hospital pain management guidelines or facilities standard 
of care.  Any rescue medications used will be provided by the study site pharmacy. 
Water, Gatorade, Powerade, Pedialite, or Popsicles will be allowed for the first hour (1 
hour) following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study.  
Subjects will undergo an End-of-Study assessment at least 24 hours after dosing with 
Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do 
so, subjects will be discharged from the study.  Subjects who discontinue the study for 
any reason will not be replaced. 
Safety will be assessed, between time 0 and 24 hours post first study medication 
administration, by monitoring AEs, clinical laboratory test results, vital sign 
measurements, temperature, pulse oximetry, and physical examination findings. 
The FLACC will be used to measure pain prior to  and 20, 40, 60, 90, 120, 180, and 240 
minutes after the dose of Oxycodone Oral Solution in subjects under 2 years of age.  The 
FLACC will also be administered prior to the subject receiving each dose of Fentanyl or 
other rescue pain medication. 
For subjects 2 to <17 years of age, serial blood samples for PK analysis will be collected 
for the determination of plasma concentrations of oxycodone at the predose time point 
(within 15 minutes of dosing); 30 (between 25-35 min), and 60 (between 50-70 min) 
minutes after dosing; and 2 (between 110-130 min), 4 (between 3-5 hrs), 6 (between 4-7 
hrs), 8 (between 6-10 hrs), 12 (between 12-18 hrs), and 24 (between 22-24 hrs) hours 
after the first dose of Oxycodone Oral Solution. For subjects under age 2, serial blood 
samples for PK analysis will be collected prior to the first dose (within 15 minutes of 


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dosing); 30 (between 25-35 min) and 60 (between 50-70 min) minutes after dosing; and 2 
(between 110-130 min), 6 (between 4-7 hrs), 12 (between 12-18 hrs), and 24 (between 
22-24 hrs) hours after dosing.  
7.2 
Discussion of Study Design 
This is an open-label, nonrandomized, multicenter study designed to assess the 
pharmacokinetics and safety of the product oxycodone hydrochloride USP oral solution, 
5 mg per 5 mL, in pediatric and adolescent subjects <17 years of age following a surgical 
procedure and expected to require postoperative opioid analgesia and an indwelling IV 
catheter after being cleared for oral intake.  Target enrollment will be 110 subjects, 
including a minimum of 20 subjects under age 2 (5 subjects ages 0 to <2 months, 5 
subjects ages 2 to <6 months, and 10 subjects ages 6 months to <2 years), 30 ages 2 to 6 
years, 30 ages 7 to 12 years and 30 ages 13 to <17 years, to evaluate safety in the 
population.  Subjects within each age group will be evenly distributed by age and gender.  
In addition, this sample size will allow for an adequate evaluable population according to 
published population PK studies in children21 and unofficial FDA guidance on sample 
size calculations based on estimates of clearance and volume of distribution.27  
Recruitment projections are based on a review of recent reports of adolescent scoliosis 
surgery showing that major specialty surgical centers average 10 to 20 patients per year 
in this age group.28-32 
7.3 
Study Sites 
The study will take place at up to 10 sites in the US. 
7.4 
Point of Contact 
A point of contact will be identified to provide subjects with information on the study, 
subject rights, and whom to contact in case of study-related injury. This information will 
be provided in the subject information and informed assent and consent forms. 
8. SUBJECT POPULATION 
8.1 
Selection of Study Population 
8.1.1 
Inclusion Criteria 
A subject will be eligible for inclusion in the study if he or she meets the following 
criteria: 
1 
Is male or female <17 years of age at the time of dosing. 
2 
Subject 2 to <17 years of age, be in at least the 25% for weight according to the 
Center for Disease Control pediatric growth charts and weighs at least 28 lb at the 
time of dosing with study drug. 
3 
Is generally healthy defined as American Society of Anesthesiologists (ASA) 
Physical Status classification grade I or II (except for the condition for which the 
procedure is being performed), documented by medical history; physical examination 


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(including, but not limited to, the cardiovascular, gastrointestinal, respiratory, and 
central nervous systems); vital sign assessments; electrocardiogram (ECG); clinical 
laboratory assessments; and general observations.   
4 
Has a negative urine pregnancy test predose (for females of childbearing potential). 
5 
Is an outpatient prior to admission for a surgical procedure and is expected to remain 
hospitalized for at least 24 hours after dosing with study drug. 
6 
Is anticipated to have postsurgical pain requiring a parenteral analgesic regimen by 
using a short-acting opioid analgesic and is anticipated to be switched to an oral 
opioid for at least 1 dose (according to institution standard of care). 
7 
Has an indwelling access catheter for blood sampling. 
8 
Agrees to comply with all protocol requirements.  If not old enough, the legally 
responsible parent(s) or legal guardian(s) must agree to comply with all protocol 
requirements. 
9 
Has been informed of the nature of the study, and informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, in accordance with institutional review 
board requirements. 
8.1.2 
Exclusion Criteria 
A subject will be excluded from the study if he or she meets the following criteria: 
1 
Has the presence or history of a clinically significant disorder involving the 
cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, 
endocrine, or neurologic system(s) or psychiatric disease (except for the condition for 
which the procedure is being performed) greater than grade II on ASA Physical 
Status classification as determined by the clinical investigator. 
2 
Has any clinical laboratory test result documented as “alert”, “critical”, or “panic” per 
institution laboratory ranges or has aspartate transaminase, alanine transaminase, or 
alkaline phosphatase > 2.0 x the upper limit of normal (ULN); total bilirubin > 1.5 x 
ULN; serum creatinine > 1.5 x ULN; or blood urea nitrogen > 1.5 x ULN. 
3 
Has a clinically significant illness (ASA Physical Status classification > II), except 
for the condition for which the procedure is being performed, in the 28 days before 
dosing with study drug as determined by the clinical investigator. 
4 
Is a lactating or breastfeeding female. 
5 
Uses any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) 
or 28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing 
with study drug.  Use of any monoamine oxidase inhibitor or St. John’s wort is 
prohibited from 28 days before dosing until 14 days after dosing.  Standard daily dose 
multivitamins (nontherapeutic doses) may be taken until enrollment into the study but 
will be restricted during the study. 


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6 
Consumes alcohol- or xanthine-containing products within 8 hours before dosing and 
during periods when blood samples are collected. 
7 
Consumes grapefruit, grapefruit products, Seville oranges, or pomelo-containing 
products within 5 days of dosing.  Fruit juices, with the exception of apple and grape, 
will be prohibited during the study. 
8 
Is a smoker or has used nicotine or nicotine-containing products within 30 days of 
dosing. 
9 
Has a history of alcohol or drug addiction or abuse within the last year.  
10 Temperature >100°F at time of initial administration of study medication. 
11 Donated blood within 28 days or plasma within 14 days of dosing or plans to donate 
them within 4 weeks after completing the study. 
12 Has a history of relevant drug allergies, food allergies, or both (i.e., allergy to 
oxycodone, allergy to related drugs, or any significant food allergy that could 
interfere with the study). 
13 Is intolerant to direct venipuncture. 
14 Received an investigational drug within 28 days of dosing. 
15 Has taken oxycodone or oxymorphone within the 48 hours before anticipated dosing 
with study drug. 
16 Is not suitable for entry into the study in the opinion of the investigator. 
8.2 
Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from participation in this study at any time for any 
reason and without prejudice. 
The investigator may terminate a subject from the study at any time for lack of 
therapeutic effect that is intolerable to the subject or otherwise considered unacceptable, 
for intolerable or unacceptable AEs, intercurrent illness, noncompliance with study 
procedures, administrative reasons, or unsuitability for the study in the investigator’s 
opinion to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate case report form (CRF).  Whenever possible and reasonable, 
evaluations that were scheduled for study completion should be performed at the time of 
premature discontinuation. 
Subjects who discontinue from the study will not be replaced. 


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9. STUDY TREATMENTS 
9.1 
Method of Assigning Subjects to Treatment Groups 
9.1.1 
Under Age 2 
Subjects under age 2 who meet all eligibility criteria will receive a single dose of 
Oxycodone Oral Solution.  This will be an open-label study and does not require 
randomization. 
9.1.2 
Ages 2 to <17 
Subjects ages 2 to <17 who meet all eligibility criteria will be scheduled to receive single 
or multiple doses of Oxycodone Oral Solution.  This will be an open-label study and does 
not require randomization. 
9.2 
Identification of Investigational Products 
The study drug is Oxycodone Oral Solution (5 mg/5 mL) manufactured by VistaPharm 
(Largo, FL).  Oxycodone Oral Solution is a red solution intended for oral administration. 
Oxycodone Oral Solution will be supplied in 500-mL bottles.  Oxycodone Oral Solution 
contains 4.5 mg of oxycodone free base per 5 mL (5 mg oxycodone HCl/5 ml) and the 
following inactive ingredients: poloxamer 188 NF, sodium benzoate NF, citric acid 
anhydrous USP, glycerin natural USP, sorbitol solution 70% USP, FD&C Red #40, 
raspberry flavor, and water. 
VistaPharm will provide an adequate supply of study drug to the sites. 
Ketorolac for injection (15 mg/mL or 30 mg/mL), Morphine Sulfate for injection (2 
mg/mL), and Fentanyl via NCA for use as a rescue medication will be provided by the 
study site pharmacy. Should other rescue medication be required they will be provided by 
the study site pharmacy. 
9.3 
Treatment Administered 
The study drug will be administered only to eligible subjects under the supervision of the 
investigator or identified subinvestigator(s). 
9.3.1 
Under Age 2 
Each subject will receive a single dose of Oxycodone Oral Solution in place of the 
standard analgesic dose after being postoperatively cleared to transition to oral pain 
medication.  The dose will be determined based on an evaluation of the safety and PK 
observed from the interim analyses.  Oxycodone Oral Solution will be administered with 
an oral medication syringe. 
9.3.2 
Ages 2 to <17 
Each subject will receive a dose of Oxycodone Oral Solution (0.1 mg/kg for children 
ages 2 to 6, 0.08 mg/kg for ages 7 to 12, and 0.07 mg/kg for ages 13 to <17) in place of 


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the standard analgesic dose after being postoperatively cleared to transition to oral pain 
medication.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age groups, 
who will be included in the first interim analysis, will only receive 1 dose of Oxycodone 
Oral Solution.  Subjects enrolled in the study after the interim analysis is completed may 
receive additional doses every 4-6 hours as needed.  Oxycodone Oral Solution will be 
administered with an oral medication syringe.   
9.4 
Storage 
Oxycodone Oral Solution will be stored in a locked facility with restricted access.  This 
may be a locked cabinet or room for which the number of keys is limited and in 
compliance with standards of the Drug Enforcement Administration for Schedule II 
narcotics.  Chain of custody of the study drug will be followed in accordance with the 
individual site’s standard procedures, which will be documented by the site and provided 
to the sponsor.  The study drug will be stored at controlled room temperature between 
20°C and 25°C (68°F-77°F).  The sponsor will provide to the site personnel instructions 
for the storage and return of used and unused study drug. 
9.5 
Labeling 
Each container of study drug will be labeled with study-specific information that meets 
all applicable regulatory requirements. 
9.6 
Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, 
or other disposition of study drug, including the date, quantity, batch or code number, and 
identification of subjects (subject number and initials) who received study drug.  The 
investigator will not supply study drug to any person except those named as 
subinvestigators on the FDA 1572, designated staff, and subjects in this study.  The 
investigator will not dispense study drug from any sites other than those listed on the 
FDA 1572.  Study drug may not be relabeled or reassigned for use by other subjects. 
Upon completion of the study, unused supplies of study drug will be reconciled by the 
investigator and returned to the sponsor as directed. 
9.7 
Blinding and Unblinding Treatment Assignment 
Not applicable. 
9.8 
Selection of Dose in the Study 
The published literature on treatment of pediatric pain with oxycodone reports doses 
ranging from 0.125 to 0.2 mg/kg, up to a maximum of 15 mg, for treatment of acute 
musculoskeletal pain, including suspected fractures in emergency room settings, for 
treatment of undifferentiated abdominal pain, and for pediatric burn wound care in 
outpatient clinics.33-36  A PK modeling has been conducted using the data derived from 
the 4 studies conducted in the adult population. Based on these population data, the test 
dose chosen for subjects ages 2 to 6 is 0.1 mg/kg, ages 7 to 12 is 0.08 mg/kg, ages 13 to 
<17 is 0.07 mg/kg, and a dose to be determined based on PK modeling from the interim 


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analyses for subjects under age 2, given when the subjects have been cleared for oral 
intake and in place of the analgesic regimen (nonoxycodone and nonoxymorphone) 
prescribed postoperatively for subjects by their attending physicians according to 
institutional SOCs.  The first 10 subjects in each of the 2 to 6, 7 to 12 and 13 to <17 age 
groups, who will be included in the first interim analysis, will only receive 1 dose of 
Oxycodone Oral Solution.  Subjects in these age groups enrolled in the study after the 
interim analysis is completed may receive additional doses every 4-6 hours as needed.   
The dose for subjects under age 2 will be determined based on an evaluation of the safety 
and PK observed from the interim analyses. 
9.9 
Selection of Timing of Dose for Each Subject 
The design of the study and the timing of dosing were selected to provide the appropriate 
basis for assessing the PK parameters of oxycodone following administration of the first 
dose. 
9.10 Treatment Compliance 
All study drugs will be administered in the hospital by study personnel and recorded in 
the CRF.  Study personnel will confirm that the subject ingests the entire dose of study 
drug. 
The date and time of study drug administration will be recorded on the appropriate page 
of the CRF.  If a subject does not receive the study drug, the reason for the missed dose 
will be recorded. 
9.11 Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate CRF. The 
medication name, dose, including frequency, date, and indication for use must be 
recorded.  Time of rescue medication will also be recorded. The medical monitor should 
be notified in advance of (or as soon as possible after) any instances in which prohibited 
therapies or rescue medications are administered.  Medications and therapies that are 
considered necessary for the subject’s welfare and will not interfere with the response to 
the study medication may be given at the discretion of the investigator. 
9.11.1 
Permitted Therapies 
Concomitant medications (with the exceptions described in Section 9.11.2) are allowed, 
but should be limited to only those medications considered necessary. 
Nausea and vomiting are common opioid-induced AEs for which subjects do develop a 
tolerance. Subjects who undergo surgery requiring opioid analgesia for an extended 
period of time may develop these AEs.  Therefore, it is expected that some subjects will 
need to be given an antiemetic. Any antiemetic used during treatment with study drug 
should be recorded as a concomitant medication. 


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9.11.2 
Prohibited Therapies 
Use of any medication known to be an inhibitor or inducer of CYP3A4 within 14 days 
(for inhibitors such as the azole-antifungal agents voriconazole and ketoconazole, 
macrolide antibiotics such as erythromycin, and protease inhibitors such as ritonavir) or 
28 days (for inducers such as rifampin, carbamazepine, and phenytoin) of dosing with 
study drug through the end of the study is prohibited.  
Use of any monoamine oxidase inhibitor or St. John’s wort is prohibited from 28 days 
before dosing until 14 days after dosing.  Standard daily dose multivitamins 
(nontherapeutic doses) may be taken until enrollment into the study but will be restricted 
during the study.   
Restrictions: 
Females of childbearing potential must be practicing abstinence or using a medically 
acceptable form of contraception (e.g., intrauterine device, hormonal birth control, or 
double-barrier method).  For the purpose of this study, all females who are menstruating 
will be considered to be of childbearing potential unless they are biologically sterile or 
surgically sterile for more than 1 year. 
Consumption of alcohol- or xanthine-containing products within 8 hours before dosing 
and during periods when blood samples are collected is prohibited.  Consumption of 
grapefruit, grapefruit products, Seville oranges, or pomelo-containing products is 
prohibited within 5 days of dosing with study drug.  All types of fruit juices, with the 
exception of apple and grape, and fruit-containing popsicles will be prohibited during the 
study. 
Subjects who smoke or use nicotine or nicotine-containing products within 30 days of 
Screening will be excluded from study participation. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for 
continuation in the study at the discretion of the sponsor, investigator, medical monitor, 
or other authority. 
9.12 Rescue Medication 
In subjects ages 2 to <17 years, if pain control is inadequate with Oxycodone Oral 
Solution, the investigator may administer an IV dose of ketorolac (0.5 mg/kg) every 
6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 hours as rescue 
medication for breakthrough pain after dosing. Use of other rescue pain medication is 
permissible in accordance with hospital pain management guidelines or facilities standard 
of care.  Any rescue medications used will be provided by the study site pharmacy. 
In subjects under age 2, if pain control is inadequate with Oxycodone Oral Solution, as 
indicated by a score of moderate to severe (4-10) on the FLACC, the subject will be 
given Fentanyl via NCA.  Use of other rescue pain medication is permissible in 
accordance with hospital pain management guidelines or facilities standard of care.  Any 
rescue medications used will be provided by the study site pharmacy.. 


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10. STUDY PROCEDURES 
Subjects’ legally responsible parent(s) or legal guardian(s) will provide written informed 
consent and subjects will provide written informed assent (as appropriate) before any 
study-related procedures are initiated, including the cessation of prohibited concomitant 
therapy. 
Table 2 (Section 17) presents the schedule of events to be performed during the study. 
10.1 Screening (Day −14 to Day 1) 
Subjects must be screened within 14 days before enrollment in the study.  The following 
procedures will be performed at Screening: 
• Obtain written informed consent and assent (as appropriate). 
• Review inclusion and exclusion criteria. 
• Collect demographic information. 
• Record medical history, including prior and current therapies (e.g. prescription 
and nonprescription medications). 
• Perform a physical examination including weight, height, body mass index, and 
vital signs (blood pressure, heart rate, respiratory rate, and temperature).   
• Perform urine pregnancy test for all females of childbearing potential. 
• Perform ECG. This may occur at the screening visit or at any time prior to study 
medication dosing. 
• Collect blood and urine samples for clinical laboratory tests (complete blood 
count with differential, clinical chemistry, serology, and urinalysis) (Section 
11.2.2). 
10.2 Predose Check-in (Predose) 
The predose check-in (Predose) can be performed the same day as surgery (Day 1) at 
which time eligibility and prior medications will be reviewed and updated as needed.  
Medical history will be recorded, if it was not completed at Screening, and vital signs 
will be obtained.  Following surgery, subjects will receive standard care, including 
parenteral analgesia with a nonoxycodone, nonoxymorphone medication that will not 
interfere with the measurement or metabolism of oxycodone. Screening and Predose 
procedures may overlap and, if so, do not need to be repeated. 
10.3 Open-Label Treatment (Day 1, After Surgery) 
The following procedures will be performed on Day 1: 
• Measure heart rate, and respiratory rate before dosing (within 90 minutes) with 
Oxycodone Oral Solution and every 15 minutes for 4 hours after dosing, then every 2 
hours until 24 hours after the first dose of Oxycodone Oral Solution. 
• Measure blood pressure before dosing (within 90 minutes) with Oxycodone Oral 
Solution and every 15 minutes for 4 hours after dosing, every 2 hours until 8 hours 


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after the first dose of Oxycodone Oral Solution, and 4 hours until 24 hours after the 
first dose of Oxycodone Oral Solution. 
• Measure temperature predose and every 2 hours for 24 hours after the first dose of 
Oxycodone Oral Solution. 
• Continuous pulse oximetry beginning  minimally 1 hour prior to transition to oral 
pain medication through 8 hours after the last study dose of Oxycodone Oral 
Solution.  The following timepoints will be captured in the CRF: predose, 5, 10, 30 
and 60 minutes, 2 hours, then every 2 hours until 8 hours after the last study dose of 
Oxycodone Oral Solution. 
• Assess pain in subjects under 2 years of age by using the FLACC prior to and 20, 40, 
60, 90, 120, 180, and 240 minutes after the first dose of Oxycodone Oral Solution.  
The FLACC will also be administered prior to the subject receiving each dose of 
Fentanyl or other rescue pain medication. 
• Record concomitant medication use. 
• Assess and record AEs prior to dosing and throughout the remainder of Day 1. 
• For subjects 2 to <17 years of age, collect serial blood samples for PK analysis at the 
predose time point (within 15 minutes of dosing); 30 (between 25-35 min), and 60 
(between 50-70 min) minutes after dosing; and 2 (between 110-130 min), 4 (between 
3-5 hrs), 6 (between 4-7 hrs), 8 (between 6-10 hrs), 12 (between 12-18 hrs), and 24 
(between 22-24 hrs) hours after the first dose of Oxycodone Oral Solution. For 
subjects under age 2, serial blood samples for PK analysis will be collected prior to 
the first dose (within 15 minutes of dosing); 30 (between 25-35 min) and 60 (between 
50-70 min) minutes after dosing; and 2 (between 110-130 min), 6 (between 4-7 hrs), 
12 (between 12-18 hrs), and 24 (between 22-24 hrs) hours after dosing. 
• After subjects ages 2 to <17 have been postoperatively cleared to transition to oral 
pain medication, Oxycodone Oral Solution will be administered at Time Zero of 
Day 1 in place of the standard analgesic medication.  The first 10 subjects in each of 
the 2 to 6, 7 to 12 and 13 to <17 age groups, who will be included in the first interim 
analysis, will only receive 1 dose of Oxycodone Oral Solution.  Subjects in these age 
groups enrolled in the study after the interim analysis is completed may receive 
additional doses every 4-6 hours as needed.  If pain control is inadequate with 
Oxycodone Oral Solution, the investigator may administer an IV dose of ketorolac 
(0.5 mg/kg) every 6 hours or an IV dose of Morphine Sulfate (0.1 mg/kg) every 4 
hours as rescue medication for breakthrough pain after dosing.  Use of other rescue 
pain medication is permissible in accordance with hospital pain management 
guidelines or facilities standard of care. 
• After subjects under age 2 have been postoperatively cleared to transition to oral pain 
medication, they will receive a single dose of Oxycodone Oral Solution at Time Zero 
of Day 1 in place of the standard analgesic medication.  The dose will be determined 
based on PK modeling from the interim analyses.  If pain control is inadequate with 
Oxycodone Oral Solution, as indicated by a score of moderate to severe (4-10) on the 


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FLACC, the subject will be given Fentanyl via NCA. Use of other rescue pain 
medication is permissible in accordance with hospital pain management guidelines or 
facilities standard of care.  Any rescue medications used will be provided by the study 
site pharmacy. 
Water, Gatorade, Powerade, and Popsicles will be allowed for the first hour (1 hour) 
following dosing, but subjects must avoid fruit juice (excluding apple and grape), 
including fruit-containing popsicles, throughout the course of the study. 
10.4 End-of-Study/Early Discontinuation 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 
24 hours after dosing with Oxycodone Oral Solution. 
The following procedures will be performed at the End-of-Study/ Early Discontinuation 
visit: 
• Measure vital signs (blood pressure, heart rate, and respiratory rate). 
• Clinical laboratory testing (complete blood count with differential and clinical 
chemistry). 
• Record concomitant medications. 
• Record AEs. 
After these procedures are performed, the study staff will determine whether it is safe for 
the subject to be discharged from the study. 


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11. STUDY ASSESSMENTS 
11.1 Pharmacokinetics 
Blood samples for PK assessments in the subjects 2 to <17 years of age will be collected 
at the predose time point (within 15 minutes of the first dose of Oxycodone Oral 
Solution); 30 (between 25-35 min), and 60 (between 50-70 min) minutes after dosing; 
and 2 (between 110-130 min), 4 (between 3-5 hrs), 6 (between 4-7 hrs), 8 (between 6-10 
hrs), 12 (between 12-18 hrs), and 24 (between 22-24 hrs) hours after the first dose of 
Oxycodone Oral Solution. For subjects under age 2, serial blood samples for PK analysis 
will be collected prior to the first dose (within 15 minutes of dosing); 30 (between 25-35 
min), and 60 (between 50-70 min) minutes after dosing; and 2 (between 110-130 min), 6 
(between 4-7 hrs), 12 (between 12-18 hrs), and 24 (between 22-24 hrs) hours after 
dosing. Time Zero is the time of the first dose of Oxycodone Oral Solution. 
The following PK parameters will be calculated: 
• Area under the plasma concentration versus time curve from Time Zero to the last 
measurable concentration (AUC0-t) 
• Area under the plasma concentration versus time curve from Time Zero to infinity 
(AUC0-inf) 
• Ratio of AUC0-t to AUC0-inf (AUC0-t/AUC0-inf) 
• Maximum measured plasma concentration (Cmax) 
• Time of the maximum measured plasma concentration (Tmax) 
• Apparent first-order terminal elimination rate constant (Kel) 
• Apparent first-order terminal elimination half-life (t1/2) 
• Apparent clearance (CL/F) 
• Volume of Distribution (V/F) 
Other PK parameters may be calculated if deemed necessary. 
11.1.1 
Sample Collection 
Blood collection will be performed using an existing indwelling access catheter (arterial 
or venous noted on CRF) at the start of the study (the use of Emla at the insertion site is 
permitted).  All catheter lines should be appropriately flushed per institutional SOC 
before each blood draw.  The 0.5-mL blood samples will be obtained and placed into 
2.0-mL K3 ethylenediamine tetra-acetic acid tubes at each blood collection time point.  
The labels for all biological sample collection and storage containers will contain, at a 
minimum, the subject's number, protocol number, collection date, and scheduled 
collection time (study hour). 


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Study Visit/Phase 
Amount Collected 
(mL) 
Number of 
Samples 
Collected 
Total Amount 
Collected per 
Subject (mL) 
Screening Serum Chemistry and Hematologya 
2.5 mL 
1 
2.5 mL 
Pharmacokinetics (2 to <17 years old) or 
0.5 mL 
9 
4.5 mL 
    Pharmacokinetics (<2 years old) 
0.5 mL 
7 
3.5 mL 
End of Study Serum Chemistry and 
Hematology 
2.5 mL 
1 
2.5 mL 
Grand Total 
-- 
-- 
14.0 – 19.5 mLb 
a Where possible, results from clinical laboratory tests performed as part of the standard of care (SOC) will be used for study 
purposes.  A separate blood draw for the clinical laboratory test portion of this protocol will occur only if the clinical laboratory 
tests as part of the SOC will not be available to coincide with the approximate time scheduled by the protocol.  Preoperative or 
intraoperative (collected before the incision) test results must be available for review by the investigator before enrolling any 
subject into the study.  Procedures for blood draws should follow institutional SOC. 
b The total includes up to 10-mL discard volume for all 9 pharmacokinetic and laboratory testing samples, for the 2 to <17 year olds.  
Total blood volume drawn for research purposes must not exceed 3% of subject’s total blood volume, which is assumed to be 
75 mL/kg.  
11.1.2 
Blood Volumes 
Existing blood draw guidelines for pediatric research suggest minimal risk is between 3% 
and 5% of total blood volume (TBV) over 24 hours or on a single draw, and TBV is 
generally estimated at 75-80 mL/kg.  For the smallest child permitted per protocol from 
ages 2 to <17 years (weight: 28 lbs or 12.7 kg), the TBV would be estimated at 952.5 ml. 
The maximum safe volume drawn would therefore be between 28 and 47 mL, based on 
minimal risk at 3-5% TBV over 24 hours.  The required 9.5 mL plus up to 10 mL of 
discard volume, or a cumulative volume of 19.5 mL, is well under the 3-5% of TBV 
guideline for the smallest eligible participant using the smallest estimation of TBV.26 For 
the child less than 2 years of age, there is a maximum of 7 serial blood samples of 0.5 mL 
each for a total of 3.5 mL, plus 2.5 mL each for standard clinical chemistry and 
hematology tests at Screening and End of Study.  The required 8.5 mL is under the 3-5% 
of TBV guideline. 
11.1.3 
Sample Processing 
Immediately after collection, the tube will be gently inverted several times to mix the 
anticoagulant with the blood sample.  The plasma fraction will be separated by placing 
the collection tube into a refrigerated centrifuge (4°C to 8°C) for 10 minutes at 
approximately 1500g or 3000 RPM.  The plasma fraction will be withdrawn by pipette 
and placed into a polypropylene freezing tube.  All sample collection and freezing tubes 
will be clearly labeled in a manner that identifies the subject and the collection time.  
Labels will be fixed to the freezing tubes in a manner that will prevent the label from 
becoming detached after freezing.  All plasma samples will be placed into a freezer at 
approximately −20°C (± 10°C) or below until transfer or shipment to the bioanalytical 
laboratory. The time between sample collection and freezer storage should not exceed 
90 minutes.  The additional blood draws for the purposes of pharmacokinetic assessment 
in this study do not pose more than a minor risk to the subjects. 


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11.1.4 
Transport of Samples 
The clinic staff will inventory the samples that are to be shipped to the bioanalytical 
laboratory.  Each shipment will contain a complete set of samples.  The second set of 
samples will not be shipped until receipt of the first shipment is confirmed.  The 
inventory record will accompany the frozen plasma samples as per standard operating 
procedures. 
For sample shipment requiring a third party courier, the samples will be packed in ample 
dry ice within a styrofoam container to ensure the samples will remain frozen for at least 
72 hours and will be shipped via express delivery to the bioanalytical facility.  Written 
notification of sample shipment will be communicated to the bioanalytical facility and the 
sponsor.  The samples will be tracked to assure arrival in a safe and timely manner. 
The shipment will be accompanied by logs showing the name of the study drug, protocol 
number, and the subject numbers and samples included in the shipment.  Documentation 
noting what the condition of the samples upon arrival at the bioanalytical laboratory is 
and whether the amount of dry ice remaining is adequate or inadequate should be 
returned to the clinic. 
The samples will be shipped frozen to PPD at the address provided in the laboratory 
manual. 
11.1.5 
Analytical Procedures 
11.1.5.1 Bioanalytical Sample Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be measured using a validated liquid chromatography–mass 
spectrometry assay method.  The validated detection range for oxycodone is 0.2 to 
125 ng/mL in human plasma. 
Samples from subjects who withdraw consent/assent or are dropped from the study will 
not be analyzed unless otherwise requested by the sponsor. 
Samples from subjects who have been dropped from the study because of emesis 
according to PPD’s standard operating procedures will not be analyzed. 
11.1.5.2 Bioanalytical Methodology 
The bioanalytical method, assay validation, and bioanalytical report for this study will be 
provided by the bioanalytical investigator.  Full validation of a sensitive assay for the 
appropriate analytes in biological fluid, including precision, accuracy, reproducibility, 
and selectivity will be included in the final report.  The bioanalytical report will include 
the stability of the frozen samples, limit of quantitation, recovery, and a summary of the 
standard curves. 


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11.2 Safety 
Safety will be assessed during the study by the monitoring and recording of AEs, clinical 
laboratory test results (hematology, biochemistry, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, and respiratory rate), 
temperature, pulse oximetry, and physical examination findings. 
11.2.1 
Adverse Events 
11.2.1.1 Adverse Event Definitions 
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation patient administered a pharmaceutical product that does not necessarily 
have a causal relationship with the product.  An AE can therefore be any unfavorable and 
unintended sign (including a new, clinically important abnormal laboratory finding), 
symptom, or disease temporally associated with the product, whether or not it is related to 
the product. 
Preexisting diseases or conditions will not be considered AEs unless there is an increase 
in the frequency or severity, or a change in the quality, of the disease or condition.  
Worsening of a preexisting condition is considered an AE. 
An expected AE is one for which the nature or severity is consistent with the known AE 
profile of the product.  For an investigational drug, the known information is contained in 
the investigator brochure.  For a marketed drug, the known information is in the current 
package insert. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current investigator brochure or package insert.  For example, hepatic necrosis would be 
unexpected (greater severity) if the investigator brochure or package insert only listed 
elevated hepatic enzymes or hepatitis.  Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the investigator brochure or 
package insert only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a 
known, already documented adverse reaction constitute unexpected AEs.  Examples 
include acute renal failure as an expected adverse reaction with a subsequent new 
occurrence of interstitial nephritis and hepatitis with a first occurrence of fulminate 
hepatitis. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly 
• Is an important medical event 


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Medical and scientific judgment should be used in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent another of the outcomes listed in the 
definition previously.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study 
drug or a hospital admission for a diagnostic evaluation of an AE does not qualify the 
condition or event as an SAE.  A newly diagnosed pregnancy in a subject who has 
received a study drug is not considered an SAE unless it is suspected that the study drug 
interacted with a contraceptive method and led to the pregnancy; however, the medical 
monitor should be made aware of a newly diagnosed pregnancy as soon as possible after 
site notification.  A congenital anomaly in an infant born to a mother who was exposed to 
the study drug during pregnancy is an SAE. 
11.2.1.2 Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 11.2.1.1) are recorded in the CRF and reported to the medical monitor 
(Section 11.2.1.3).  Adverse events will be collected from the time of the first dose of 
Oxycodone Oral Solution through the End of Study or Early Discontinuation visit. 
At each visit, subjects will be asked a standard question to elicit any medically related 
changes in their well-being.  They will also be asked if they have had any accidents, used 
any new medications, or changed concomitant medication regimens (both prescription 
and over-the-counter medications).  In addition to subject observations, AEs will be 
documented from any data collected on the AE page of the CRF (e.g., clinical laboratory 
values, physical examination findings, and ECG changes) or other documents that are 
relevant to subject safety. 
11.2.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the 
CRF.  Information to be collected includes drug treatment, type of event, time of onset, 
dose, investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome.  Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, reactions to concurrent medications, or progression of disease states must also 
be reported.  All AEs will be followed to adequate resolution.  The latest version of the 
Medical Dictionary of Regulatory Activities will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 


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The investigator or designee must report any AE that meets the criteria for an SAE 
(Section 11.2.1.1) to the medical monitor within 24 hours of first becoming aware of the 
event by telephone.  At the time of first notification, the investigator or designee should 
provide at a minimum the following information if available: 
• Protocol number 
• Subject’s study identification and initials 
• Subject’s date of birth 
• Date of dose of study drug 
• Time and date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
Within 24 hours of the initial telephone notification, the investigator must fax a written 
SAE report form to the medical monitor.  Any missing or additional relevant information 
about the SAE should be provided in a written follow-up SAE report form.  The 
investigator should also ensure that any additional information requested about the event 
(e.g., hospital reports, autopsy reports) is provided as soon as it is available. 
The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of the institutional review board (IRB). 
The following contact information is to be used for SAE reporting: 
 
Thomas J. Hochadel, Pharm.D. 
Cognitive Research Corporation 
200 Central Ave, Suite 1230 
Saint Petersburg, FL 33701 
Telephone: 727-897-9000 
Cell: 727-515-1334 
Fax: 727-897-9000 
11.2.1.3.1 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which it affects the subject’s 
daily activities.  Severity will be rated as mild, moderate, or severe using the following 
criteria: 
Mild: 
Is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere 
with usual activities of daily living. 
Moderate: 
Is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent 
risk of harm to the subject. 
Severe: 
Interrupts usual activities of daily living, significantly affects 


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clinical status, or may require intensive therapeutic intervention 
Changes in the severity of an AE should be documented to allow assessment of the 
duration of the event at each level of intensity to be performed.  Adverse events 
characterized as intermittent require documentation of onset and duration of each 
episode. 
11.2.1.3.2 Assessment of Relationship 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will 
be characterized using the following classification and criteria: 
Not related: 
An AE with sufficient evidence to accept that there is no causal 
relationship to administration of study drug (e.g., no temporal 
relationship because the study drug was administered after the 
onset of the event, an investigation shows that study drug was 
not administered, another cause was proven.) 
Unlikely related: 
An AE, including a clinical laboratory test abnormality, with a 
temporal relationship to administration of study drug that makes 
a causal relationship improbable and in which other drugs, 
events, or underlying disease provide plausible explanations. 
Possibly related: 
An AE with a reasonable time sequence to administration of 
study drug but that could also be explained by concurrent 
disease or other drugs or events.  Information on drug 
withdrawal may be lacking or unclear. 
Related: 
An AE occurring in a plausible time relationship to 
administration of study drug and that cannot be explained by a 
concurrent disease or other drugs or events.  The response to 
withdrawal of the drug (dechallenge) is clinically reasonable. 
11.2.1.3.3 Definition of Adverse Event Start Date, Stop Date, and Duration  
Start date: 
The date at which the AE is first noted 
Stop date: 
The date at which the AE is known to be resolved.  If it has not known 
to have stopped, then indicate “ongoing.” 
Duration: 
A time in days, hours, or minutes 


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11.2.1.3.4 Action(s) Taken 
Action(s) taken may consist of the following (as appropriate): 
None: 
No actions taken. 
Discontinued study 
drug: 
Study drug was permanently discontinued because of the AE. 
Treatment:  
Specified medication (to be listed on the concomitant medication 
chart) was used as a countermeasure. 
Others: 
Other actions, such as an operative procedure, were required 
because of the AE. 
11.2.1.3.5 Definition of Adverse Event Outcome at the Time of Last Observation 
The AE outcome at the time of last observation will be classified as “resolved,” “resolved 
with sequelae,” “ongoing,” “death,” “other,” or “unknown.” 
“Death” should only be selected as an outcome when the AE resulted in death.  If more 
than 1 AE is possibly related to the subject’s death, the outcome of death should be 
indicated for each such AE.  Although “death” is usually an event outcome, events such 
as sudden death or unexplained death should be reported as SAEs. 
11.2.1.4 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after dosing with study drug) to a 
satisfactory resolution or until the investigator deems the event to be chronic or not 
clinically significant or the subject to be stable.  All findings relevant to the final outcome 
of an AE must be reported in the subject’s medical record and recorded on the 
appropriate CRF. 


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11.2.2 
Laboratory Safety Assessments 
Samples for the following laboratory tests will be collected at the time points specified in 
the Schedule of Events (Section 17). 
Hematology: 
Consists of complete blood count (hemoglobin, hematocrit, 
white blood cell count with differential, red blood cell 
count, and platelet count) 
Serum chemistry: 
Includes blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase), alanine 
aminotransferase (serum glutamic pyruvic transaminase), 
glucose (fasting), albumin, and total protein 
 
 
Urinalysis: 
Includes pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrites, leukocytes, urobilinogen, 
microscopic urine analysis if dipstick positive 
Urine pregnancy test: 
Conducted for females of childbearing potential only 
Each safety laboratory assessment blood sample will be 2.5 mL in volume. The total 
amount of blood to be drawn will be a maximum of 19.5 mL per subject, including 9 
samples for PK assessments (0.5 mL each). 
11.2.3 
Vital Signs 
Vital signs, including heart rate, respiratory rate, and blood pressure will be measured at 
the time points specified in the schedule of events (Section 17) after the subject has been 
in a sitting or supine position for 5 minutes.  Body temperature will also be measured. 
11.2.4 
Pulse Oximetry 
Continuous pulse oximetry will begin minimally 1 hour prior to transition to oral pain 
medication and will continue until 8 hours after the last study dose of Oxycodone Oral 
Solution.  The following timepoints will be captured in the CRF: 5, 10, 30 and 60 
minutes, 2 hours, then every 2 hours until 8 hours after the last study dose of Oxycodone 
Oral Solution. 
11.2.5 
Electrocardiogram 
An ECG will be performed pre-dose. This may occur at Screening or any time pre-dose, 
including intra-op. 
11.2.6 
Physical Examination 
A standard physical examination will be performed at Screening or any time pre-dose, 
including intra-op.  The examination will include assessment of skin, head, ears, eyes, 
nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and 
musculoskeletal system/extremities.  Interim physical examinations will be performed at 


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the investigator’s discretion if necessary to evaluate AEs or clinical laboratory 
abnormalities. 
11.3 Faces, Legs, Activity, Crying, Consolability Scale (FLACC) 
The Faces, Legs, Activity, Crying, Consolability Scale (FLACC) (See Attachment 17.4) 
will be used to measure pain in subjects under age 2 prior to and 20, 40, 60, 90, 120, 180, 
and 240 minutes after the dose of Oxycodone Oral Solution.  The FLACC will also be 
administered prior to the subject receiving each dose of Fentanyl or other rescue pain 
medication. 
The FLACC provides a simple framework for quantifying pain behaviors in children who 
are unable to verbalize the presence or severity of pain.37 
Additionally, time of rescue medication will also be evaluated. 
12. STATISTICAL METHODS 
12.1 General Considerations 
Descriptive statistics will be provided for all demographic, safety, and PK parameters.  
No formal statistical testing will be performed for this study. 
A statistical analysis plan (SAP) that describes the details of the analyses to be conducted 
will be written before database lock. 
12.2 Analysis Populations 
The following analysis populations are planned for this study: 
• PK Population: the PK population will consist of all subjects who receive the 
study drug and have at least 1 measureable plasma concentration. 
• PK Parameter Population: all subjects who receive study drug and for which at 
least one PK parameter can be determined. 
• Safety Population: the safety population will consist of all subjects who receive 
the study drug. 
12.3 Statistical Analyses 
12.3.1 
Subject Disposition and Demographic Characteristics 
For categorical variables, frequencies and percentages will be presented.  Continuous 
variables will be summarized by using descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized.  The number of 
subjects who enroll in the study and the number and percentage of subjects who complete 
the study will be presented.  The frequency and percentage of subjects who withdraw or 
discontinue from the study, along with the reason for withdrawal or discontinuation, will 
also be summarized. 


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12.3.2 
Pharmacokinetic Analyses 
Oxycodone and its metabolites (noroxycodone, oxymorphone and noroxymorphone) 
plasma concentrations will be listed and summarized.  Each subject’s oxycodone plasma 
concentrations will be graphed using both a normal scale y-axis and a logarithmic scale 
y-axis.  Mean oxycodone plasma concentrations for each age group will also be graphed 
using scheduled elapsed sampling times for both the normal and logarithmic scale y-axis. 
Pharmacokinetic parameters will be listed for each subject and summarized by group.  
Key PK parameters will be contrasted with adult values from the previously conducted 
PK studies. 
Other PK analyses may be performed as appropriate. 
12.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and will be summarized 
overall.  Adverse events will also be summarized by severity and relationship to study 
drug.  Serious AEs and AEs leading to discontinuation of study drug will also be 
summarized. 
Actual values and changes from Baseline for clinical laboratory results, vital sign 
measurements, temperature, and pulse oximetry will be summarized at each time point 
using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) or shift tables where appropriate.  Physical examination findings will be 
presented in a listing. 
12.3.4 
Exploratory Analyses 
The change from baseline in total FLACC Score will be summarized at each time point.  
The total amount of Fentanyl or other rescue pain medication will also be evaluated. 
12.3.5 
Interim Analyses 
An interim analysis will be run after 10 subjects ages 2 to 6 years, 10 ages 7 to 12 years 
and 10 ages 13 to <17 years have completed the study.  The interim analysis will include 
PK, pulse oximetry readings, vital sign measurements, adverse events (AEs) and 
concomitant medications.  The dose of Oxycodone Oral Solution that the subjects ages 6 
months to <2 years will receive will be based on an evaluation of the safety and PK 
observed from this interim analysis. 
An additional interim analysis will be run after at least half of the subjects aged 6 months 
to <2 years have completed the study.  The interim analysis will include PK, pulse 
oximetry readings, vital sign measurements, AEs and concomitant medications.  The dose 
of Oxycodone Oral Solution that the subjects ages 0 to <2 months and 2 months to <6 
months will receive will be based on  an evaluation of the safety and PK observed from 
this interim analysis. 


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12.4 Sample Size Determination 
The evaluable sample size for this study is powered to target a 95% confidence interval 
within 60% and 140% of the geometric mean estimates of clearance and volume of 
distribution for oxycodone with at least 80% power. 
Estimates of the coefficient of variation for the clearance and volume of distribution of 
oxycodone were 25.72% and 71.12%, respectively, and were based on estimated standard 
deviations of (log-transformed) clearance and volume as provided in a June 28, 2012 PK 
modeling technical report.  The above mentioned values for % coefficient of variation 
(%CV) are derived using the approximation: 
 
, 
 
where SD are the standard deviations given in the technical report, with values of 0.2531 
and 0.6398 for clearance and volume, respectively.  The methodology for samples size 
calculation is as given in Wang, et al.27   
Because of an anticipated dropout rate of 33%, a recruited sample size of 30 subjects is 
considered sufficient to ensure 20 evaluable subjects to assess the PK profiles of 
Oxycodone Oral Solution. 
While the PK analysis will require a recruited sample size of 30 subjects, the trial will 
enroll 110 subjects to gather adequate safety information. 
13. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the 
investigator and associated personnel prior to the study, periodic monitoring visits, and 
meticulous data management. 
13.1 Sponsor and Investigator Responsibilities 
13.1.1 
Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15).  The sponsor reserves the right to withdraw a subject from the study 
(Section 8.2), to terminate participation of a study site at any time (Section 13.7), or to 
discontinue the study (Section 13.6.2). 
The sponsor agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
13.1.2 
Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.3), the investigator indicates that he 
or she has carefully read the protocol, fully understands the requirements, and agrees to 


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conduct the study in accordance with the procedures and requirements described in this 
protocol. 
The investigator also agrees to conduct this study in accordance with all laws, 
regulations, and guidelines of the pertinent regulatory authorities, including and in 
accordance with the April 1996 ICH Guidance for Industry E6 Good Clinical Practice 
(GCP) and in agreement with the 1996 Version of the Declaration of Helsinki.  While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing 
the study and for ensuring compliance with the protocol and all applicable regulations 
and guidelines.  The investigator is responsible for maintaining a list of all persons that 
have been delegated study-related responsibilities (e.g., sub-investigators and study 
coordinators) and his or her specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, 
and their specific duties within the context of the study.  Investigators are responsible for 
providing the sponsor with documentation of the qualifications, GCP training, and 
research experience for themselves and their staff as required by the sponsor and the 
relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent 
person.  The investigator agrees, by written consent to this protocol, to cooperate fully 
with compliance checks by allowing access to all study documentation by authorized 
individuals. 
13.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving 
notification from the sponsor or its designee that the study can be initiated at the study 
site.  The study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed assent and consent. 
2. All GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 


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13.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study.  
Subjects may only be rescreened once 30 days or more after the original Screening visit.  
If a subject is eligible to enter the study after having previously failed screening, he or 
she will be assigned a new subject identification number. 
13.4 Study Documents 
All documentation and material provided by the sponsor for this study are to be retained 
in a secure location and treated as confidential material. 
13.4.1 
Good Clinical Practice Documents 
The GCP documents are listed below. 
• Signed original protocol; (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and sub-investigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• FDA Form 1572 
• Any other relevant GCP documents 
The GCP documents must be received from the investigator and reviewed and approved 
by the sponsor or designee before the study site can initiate the study and before the 
sponsor will authorize shipment of study drug to the study site.  Copies of the 
investigator’s GCP documents must be retained at the study site in a secure location.  
Additional documents, including a copy of the protocol and applicable amendment(s), the 
study drug, CRF completion guidelines, copies of regulatory references, copies of IRB 
correspondence, and study drug accountability records should also be retained as part of 
the investigator’s GCP documents.  It is the investigator’s responsibility to ensure that 
copies of all required GCP documents are organized, current, and available for 
inspection. 
13.4.2 
Case Report Forms 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to 
maintain accurate CRFs and source documentation as part of the case histories for all 
subjects whose legally responsible parent(s) or legal guardian(s) sign an informed 
consent form and subjects who sign assent (as appropriate). 
Case report forms are considered confidential documents and should be handled and 
stored accordingly.  The sponsor or its designee will provide the necessary training on the 
use of the specific CRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 


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To ensure data accuracy, CRF data for individual subject visits should be completed as 
soon as possible after the visit.  All requested information must be entered in the 
electronic data capture (EDC) system, if applicable, according to the completion 
guidelines provided by the sponsor or its designee. 
The CRFs may be signed by the investigator or a subinvestigator.  These signatures serve 
to attest that the information contained in the CRF is accurate and true. 
13.4.3 
Source Documents 
All information recorded in the EDC system must be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory notes, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files.  
Before the study starts, a list identifying any data to be recorded directly on the CRFs 
(i.e., no prior written or electronic record of data) and considered to be source data will 
be provided. 
Clinical laboratory data required by the protocol will be electronically transferred from 
the central laboratory to the sponsor or its designee. A paper copy of the laboratory 
results will be provided to the study site and should be retained with each subject’s 
source data. 
13.5 Data Quality Control 
The sponsor and its designees will perform quality control checks on this clinical study. 
13.5.1 
Monitoring Procedures 
The sponsor or designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines.  The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study site 
at periodic intervals and maintain periodic communication.  The investigator agrees to 
allow the CRA(s) and other authorized sponsor personnel access.  The CRA(s) will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. While on site, the CRA(s) will review: 
• Regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• Consenting procedures 
• AE procedures 
• Storage and accountability of study drug and study materials 


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The CRA will ask for clarification or correction of any noted inconsistencies.  Procedures 
for correcting CRFs are described in the study manual.  As representatives of the sponsor, 
CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.3), the investigator agrees to meet 
with the CRA(s) during study site visits; to ensure that study staff is available to the 
CRA(s) as needed; to provide the CRA(s) access to all study documentation, to the 
clinical supplies dispensing and storage area; and to assist the monitors in their activities, 
if requested.  Further, the investigator agrees to allow the sponsor or designee auditors or 
inspectors from regulatory agencies to review records and to assist the inspectors in their 
duties, if requested. 
13.5.2 
 ata Management 
 he sponsor or designee will be responsible for activities associated with the data 
management of this study.  The standard procedures for handling and processing records 
will be followed per GCP and the sponsor’s or CRO’s standard operating procedures.  A 
comprehensive data management plan will be developed including a data management 
overview, database contents, annotated CRF, pre-entry review list, self-evident correction 
conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to 
data queries are described in the study manual. 
13.5.3 
Quality Assurance/Audit 
This study will be subject to audit by the sponsor or designee.  The audits will be 
undertaken to check compliance with GCP guidelines and will include a minimum of: 
• In-house study file audit 
• Audit of computer database quality control 
• Audit of clinical report quality control 
The sponsor or designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used 
for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities 
according to GCP guidelines.  The investigator agrees to cooperate with the auditor 
during the visit and will be available to supply the auditor with CRFs or other files 
necessary to conduct that audit.  Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, 
the investigator shall notify the sponsor immediately. 


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13.6 Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. 
13.6.1 
Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject 
out or last subject last visit) participating in the study.  Within 90 days of the end of the 
clinical study, the sponsor or designee will notify the IRB and regulatory authorities 
about the regular termination of the study as required. 
13.6.2 
Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by the sponsor, 
IRB, regulatory authorities, or the coordinating investigator.  A decision to prematurely 
terminate the study is binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, the sponsor or designee will 
notify the IRB and regulatory authorities as required. The sponsor or designee must 
clearly explain the reasons for premature termination. 
If the study is terminated prematurely, all investigators must inform their subjects and 
take care of appropriate follow-up and further treatment of subjects to ensure protection 
of the subjects’ interests.  Study sites may be asked to have all subjects currently 
participating in the study complete all of the assessments for the Early Termination visit. 
13.7 Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor may terminate 
participation of a study site at any time.  Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol, applicable regulations and guidelines, or both 
• Inadequate subject enrollment 
13.7.1 
Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until at 
least 2 years after the notification of submission of the final study report to regulatory 
authorities by the sponsor. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 


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After completing the study, the sponsor will be provided with the original CRFs or at 
least a legible copy and retain the documents at least 5 years after the completion of the 
study. 
One copy will remain with the investigator.  The investigator shall arrange for the 
retention of the subject identification codes, subject files, and other source data until at 
least 5 years after notification of submission of the final study report to the regulatory 
authorities by the sponsor.  These documents need to be retained for a longer period of 
time if required by applicable regulatory authorities or by agreement with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor shall have 30 days to respond to the 
investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) 
shall be kept by the investigator for the maximum period of time permitted by the 
hospital, institution, or private practice. 
13.7.2 
Sample Retention 
Samples may be used for purposes related to this research.  The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision 
has been made that none of the samples needs to be reanalyzed.  In addition, identifiable 
samples can be destroyed at any time at the request of the subject. 
13.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, 
which requires the written approval by the sponsor.  The protocol amendment must be 
signed by the investigator and approved by the IRB before it may be implemented.  
Protocol amendments will be filed with the appropriate regulatory agency. 
13.9 Use of Information and Publication 
All information about the study drug, the sponsor’s operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by the sponsor or designee to the investigator and not previously published, is 
considered confidential and remains the sole property of the sponsor.  Case report forms 
also remain the property of the sponsor.  The investigator agrees to use this information 
for purposes of study execution through finalization and will not use it for other purposes 
without the written consent of the sponsor. 
The information developed in this study will be used by the sponsor in connection with 
the continued development of the study drug and thus may be disclosed as required to 
other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of the sponsor.  Publication or 
other public presentation of study drug data resulting from this study requires prior 
review and written approval of the sponsor.  Abstracts, manuscripts, and presentation 


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materials should be provided to the sponsor for review and approval at least 30 days prior 
to the relevant submission deadline.  Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, 
poster exhibition, or publication by the investigator until the sponsor has reviewed, 
commented on, and authorized such a presentation or manuscript for publication. 
14. FINAL CLINICAL STUDY REPORT 
The sponsor will retain ownership of the data from this study. 
The final CSR will be written within 1 year of completion of the clinical part of the study.  
This report will include a summary of the study results based on a statistical evaluation 
and clinical assessment of the protocol-defined endpoints. 
The final CSR will be submitted to the regulatory authorities. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents) and the 
1996 Version of the Declaration of Helsinki. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the 
investigator’s informed assent and consent documents, and related subject information 
and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that informed consent and assent (as 
appropriate) have been obtained from the legally responsible parent(s) or legal 
guardian(s) and the subject, respectively, before any activity or procedure is undertaken 
that is not part of routine care. 
15.3 Approval by Institutional Review Board 
A valid IRB must review and approve this protocol before study initiation.  Written 
notification of approval is to be submitted by the investigator to the sponsor monitor 
before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature.  This written approval must consist 
of a completed sponsor IRB Approval Form or written documentation from the IRB 
containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval 
from the IRB, or a designee, must be received by the sponsor before implementation.  


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This written approval will consist of a completed IRB Approval form or written 
documentation from the IRB containing the same information. 


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16. REFERENCES 
 
1 
Andreassen TN, Klepstad P, Davies A, et al. Influences on the pharmacokinetics of oxycodone: a 
multicentre cross-sectional study in 439 adult cancer patients. Eur J Clin Pharmacol. 
2011;67:493-506. 
2 
Benziger DP, Kaiko RF, Miotto JB, Fitzmartin RD, Reder RF, Chasin M. Differential effects of 
food on the bioavailability of controlled-release oxycodone tablets and immediate-release 
oxycodone solution. J Pharm Sci. 1996;85:407-410. 
3 
Davis MP, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman R. Normal-release and 
controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support 
Care Cancer. 2003;11:84-92. 
4 
Foral PA, Ineck JR, Nystrom KK. Oxycodone accumulation in a hemodialysis patient. South Med 
J. 2007;100:212-214. 
5 
Gammaitoni AR, Davis MW. Comparison of the pharmacokinetics of oxycodone administered in 
three Percocet formulations. J Clin Pharmacol. 2002;42:192-197. 
6 
Grönlund J, Saari TI, Hagelberg NM, Neuvonen PJ, Olkkola KT, Laine K. Exposure to oral 
oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by 
inhibition of CYP2D6 alone. Br J Clin Pharmacol. 2010;70:78-87. 
7 
Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and 
pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998;64:603-611. 
8 
Kapil R, Nolting A, Roy P, Fiske W, Benedek I, Abramowitz W. Pharmacokinetic properties of 
combination oxycodone plus racemic ibuprofen: two randomized, open-label, crossover studies in 
healthy adult volunteers. Clin Ther. 2004;26:2015-2025. 
9 
Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic 
patients undergoing renal transplantation. J Clin Anesth. 1996;8:13-18. 
10 
Kokubun H, Fukawa M, Matoba M, Hoka S, Yamada Y, Yago K. Pharmacokinetics and variation 
in the clearance of oxycodone and hydrocotarnine in patients with cancer pain. Biol Pharm Bull. 
2007;30:2173-2177. 
11 
Kummer O, Hammann F, Moser C, Schaller O, Drewe J, Krähenbühl S. Effect of the inhibition of 
CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin 
Pharmacol. 2011;67:63-71. 
12 
Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and 
pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active 
metabolites. Clin Pharmacol Ther. 2006;79:461-479. 
13 
Leow KP, Cramond T, Smith MT. Pharmacokinetics and pharmacodynamics of oxycodone when 
given intravenously and rectally to adult patients with cancer pain. Anesth Analg. 1995;80:296-
302. 
14 
Leow KP, Smith MT, Watt JA, Williams BE, Cramond T. Comparative oxycodone 
pharmacokinetics in humans after intravenous, oral, and rectal administration. Ther Drug Monit. 
1992;14:479-484. 
15 
Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother. 
2004;18:17-30. 


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16 
Olesen AE, Upton R, Foster DJ, et al. A pharmacokinetic and pharmacodynamic study of oral 
oxycodone in a human experimental pain model of hyperalgesia. Clin Pharmacokinet. 
2010;49(:817-827. 
17 
Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of 
its use in the management of pain. Curr Med Res Opin. 2008;24:175-192. 
18 
Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the 
pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010;160:907-918. 
19 
Staahl C, Upton R, Foster DJ, et al. Pharmacokinetic-pharmacodynamic modeling of morphine 
and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. 
J Clin Pharmacol. 2008;48:619-631. 
20 
Pokela ML, Anttila E, Seppälä T, Olkkola KT. Marked variation in oxycodone pharmacokinetics 
in infants. Paediatr Anaesth. 2005;15:560-565. 
21 
El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 
6 months to 7 years old. J Clin Pharmacol. 2006;46:433-442. 
22 
Kalso E. Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative 
children. Br J Clin Pharmacol. 1995;39:214-215. 
23 
Kokki H, Rasanen I, Lasalmi M, et al. Comparison of oxycodone pharmacokinetics after buccal 
and sublingual administration in children. Clin Pharmacokinet. 2006;45:745-754. 
24 
Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanpera I. Pharmacokinetics of 
oxycodone after intravenous, buccal, intramuscular and gastric administration in children. Clin 
Pharmacokinet. 2004;43:613-622. 
25 
Olkkola KT, Hamunen K, Seppälä T, Maunuksela EL. Pharmacokinetics and ventilatory effects of 
intravenous oxycodone in postoperative children. Br J Clin Pharmacol. 1994;38:71-76. 
26 
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. Jan 1 2011;89(1):46-53. 
27 
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size 
when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2011. doi: 
10.1177/0091270011422812 
28 
Aleissa S, Parsons D, Grant J, Harder J, Howard J. Deep wound infection following pediatric 
scoliosis surgery: incidence and analysis of risk factors. Can J Surg. 2011;54:263-269. 
29 
Canavese F, Turcot K, De Rosa V, de Coulon G, Kaelin A. Cervical spine sagittal alignment 
variations following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. 
Eur Spine J. 2011;20:1141-1148. 
30 
Hwang SW, Samdani AF, Tantorski M, et al. Cervical sagittal plane decompensation after surgery 
for adolescent idiopathic scoliosis: an effect imparted by postoperative thoracic hypokyphosis. J 
Neurosurg Spine. 2011;15:491-496. 
31 
Ipp L, Flynn P, Blanco J, et al. The findings of preoperative cardiac screening studies in 
adolescent idiopathic scoliosis. J Pediatr Orthop. 2011;31:764-766. 
32 
Oto M, Shah SA, Mohammed MA, Rogers KJ, Yorgova P, Holmes L. Effectiveness and safety of 
posterior titanium instrumentation in children with adolescent idiopathic scoliosis: a prospective 
study. Eklem Hastalik Cerrahisi. 2011;22:124-128. 
33 
Charney RL, Yan Y, Schootman M, Kennedy RM, Luhmann JD. Oxycodone versus codeine for 
triage pain in children with suspected forearm fracture: a randomized controlled trial. Pediatr 
Emerg Care. 2008;24:595-600. 


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34 
Kokki H, Lintula H, Vanamo K, Heiskanen M, Eskelinen M. Oxycodone vs placebo in children 
with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of 
analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med. 2005;159:320-325. 
35 
Miner JR, Moore J, Gray RO, Skinner L, Biros MH. Oral versus intravenous opioid dosing for the 
initial treatment of acute musculoskeletal pain in the emergency department. Acad Emerg Med. 
2008;15:1234-1240. 
36 
Sharar SR, Carrougher GJ, Selzer K, O'Donnell F, Vavilala MS, Lee LA. A comparison of oral 
transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care 
Rehabil. 2002;23:27-31. 
37 
Malviya S, Merkel SI, Shayevitz JR, Voepel-Lewis T. The FLACC: a behavioral scale for scoring 
postoperative pain in young children. Pediatric Nursing. 1997;23(3):293-297. 
 


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17. ATTACHMENTS 
17.1 Schedule of Events 
Table 2: 
Schedule of Events 
 
 
 
 
STUDY PROCEDURES 
Screening 
(Day −14 to 1) 
OUTPATIENT 
HOSPITALIZATION 
 
 
End of 
Study/Early 
Discontinuationb 
Predose 
Check-in 
(Predose) a 
Treatment 
(Day 1, 
Time Zero) 
Informed consent/assent 
X 
 
 
 
Eligibility (inclusion/exclusion) 
X 
X 
 
 
Prior medication assessment 
X 
X 
 
 
Medical history 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
Temperature 
X 
 
X 
 
Pulse Oximetry 
 
 
X 
 
FLACC 
 
 
X 
 
Physical examinationc 
X 
 
 
 
Clinical laboratory testsd 
X 
 
 
X 
Urine pregnancy test (females) 
X 
X 
 
 
Safety electrocardiogram 
X or 
X 
 
 
Study drug administration 
 
 
X 
 
Pharmacokinetic sampling 
 
 
X 
 
Adverse event assessment 
 
 
Xe 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
a 
The predose check-in (Predose) can be performed the same day as surgery (Day 1).  At the predose 
check-in, eligibility and prior medications will be reviewed and updated as needed.  Medical history 
will be recorded if it was not completed at Screening. 
b 
Subjects will undergo an End-of-Study/Early Discontinuation assessment at least 24 hours after dosing 
with Oxycodone Oral Solution.  At that time, if the study staff determines that it is safe to do so, 
subjects will be discharged from the study.  
c 
The physical examination will include measurements of height, weight, and body mass index. 
d 
Complete blood count with differential and clinical chemistry will be performed at Screening and End 
of Study/Early Discontinuation.  Urinalysis will be performed at Screening only. 
e 
During the study, subjects will be asked about adverse events.  If an adverse event occurs, clinic staff 
may advise the subject to remain at the hospital until a decision is made that it is safe for the subject to 
be discharged. 


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17.2 Treatment Day Procedures 
Table 3: 
Treatment Day Procedures 
Time, related to 1st dose of 
Oxycodone Oral Solution 
Pre-
dose 
0 min 
5 min 
10 min 
15 min 
30  min 
45 min 
60 min 
1 hr   
15 min 
1 hr   
30 min 
1 hr   
45 min 
2 hr 
2 hr   
15 min 
2 hr   
30 min 
2 hr   
45 min 
Vital signs (BP, HR, Resp.) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pulse oximetrya 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (Under age 2) 
Xb 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
PK sampling (2 to <17) 
Xb 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Study drug administrationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FLACCd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time, related to 1st dose of 
Oxycodone Oral Solution 
3 hr 
3 hr   
15 min 
3 hr   
30 min 
3 hr   
45 min 
4 hr 
6 hr 
8 hr 
10 hr 
12 hr 
14 hr 
16 hr 
18 hr 
20 hr 
22 hr 
24 hr 
HR, Resp.a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure (BP) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Temperature 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrya 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
PK sampling (Under age 2) 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
PK sampling (2 to <17) 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
X 
Study drug administrationc 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
FLACCd 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
AE evaluatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con meds querye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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a Pulse oximetry will begin minimally 1 hour prior to transition to oral pain medication and will continue until 8 hours after the last study dose.  The following timepoints will be captured in the CRF: 5, 
10, 30 and 60 minutes, 2 hours, then every 2 hours until 8 hours after the last dose of Oxycodone Oral Solution. 
b Blood samples for pharmacokinetic assessment will be collected at the predose time point (within 15 minutes of dosing);  
c The study drug will be administered after the surgery when subjects have been postoperatively cleared to transition to oral pain medication in place of the standard analgesic medication.  If pain control 
is inadequate with study drug, the investigator may administer rescue medication for breakthrough pain after dosing. 
d The FLACC will also be administered prior to the subject receiving each rescue dose of Fentanyl or other rescue pain medication. 
e AEs and Con Meds will be monitored throughout the course of the study. 
 
 
 


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17.3 Investigator’s Agreement 
 
PROTOCOL NUMBER: 
2012O004 
PROTOCOL TITLE: 
A PHASE IV STUDY TO EVALUATE THE SAFETY 
AND PHARMACOKINETICS OF OXYCODONE 
ORAL SOLUTION IN PEDIATRIC AND 
ADOLESCENT SUBJECTS 
FINAL PROTOCOL: 
AMENDMENT #1; 11 July 2013 
AMENDMENT #2; 18 September 2013 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein.  I will 
ensure that all subinvestigators and other study staff members have read and understand 
all aspects of this protocol.  I agree to cooperate fully with VistaPharm, Inc. and Lehigh 
Technologies, Inc., or designee during the study.  I will adhere to all FDA, ICH, and 
other applicable regulations and guidelines regarding clinical trials on an investigational 
product during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 


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17.4 Faces, Legs, Activity, Cry, Consolability Scale (FLACC) 
 
Categories 
Scoring 
 
0 
1 
2 
Face 
No particular 
expression or smile 
Occasional grimace 
or frown, withdrawn, 
disinterested 
Frequent to constant 
quivering chin, 
clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, 
tense 
Kicking, or legs 
drawn up 
Activity 
Lying quietly, 
normal position, 
moves easily 
Squirming, shifting 
back and forth, tense 
Arched, rigid or 
jerking 
Cry 
No cry, (awake or 
asleep) 
Moans or whimpers; 
occasional complaint 
Crying steadily, 
screams or sob, 
frequent complaints 
Consolability 
Content, relaxed 
Reassured by 
occasional touching, 
hugging or being 
talked to, distractible 
Difficult to console 
or comfort 
 


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18. APPENDICES 
A. Address List 
B. OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved Label 
and Full Prescribing Information 


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A. 
Address List 
18.1.1 
Sponsors 
Name: 
VistaPharm, Inc. 
Address: 
7256 Ulmerton Road 
 
Largo, FL 33771 
Phone: 
(727) 530-1633 
Fax: 
(727) 531-5427 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
Name: 
Lehigh Valley Technologies, Inc. 
Address: 
514 North 12th Street 
 
Allentown, PA 18102 
Phone: 
(610) 782-9780 
 
 
Project Manager: 
Melissa L. Goodhead, MSc, RAC  
President  
Pharmaceutical Project Solutions, Inc. 
 
18.1.2 
Clinical Research Organization 
Name: 
Cognitive Research Corporation 
Address: 
200 Central Avenue, Suite 1230 
 
Saint Petersburg, FL 33703 
Phone: 
(727) 897-9000 
Fax: 
(727) 897-9009 
Project Manager: 
Eva M. Kemper, MSHS 
Director, Clinical Projects 
 
 


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B. 
OXYCODONE HYDROCHLORIDE USP ORAL SOLUTION, Approved 
Label and Full Prescribing Information 
 


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A PHASE IV STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY 
OF OXYCODONE ORAL SOLUTION IN PEDIATRIC AND ADOLESCENT 
SUBJECTS 
 
PROTOCOL DATE: 
Version 7.1, Final 25 April 2013 
Amendment #1, 11 July 2013 
Amendment #2, 18 September 2013 
Amendment #3, 8 April 2014 
 
SPONSORED BY: 
VistaPharm, Inc. 
7256 Ulmerton Road 
Largo, FL 33771 
Phone:  (727) 530-1633 
 
 
Lehigh Valley Technologies, Inc. 
514 North 12th Street 
Allentown, PA 18102 
Phone:  (610) 782-9780 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
Cognitive Research Corporation
200 Central Avenue, Suite 1230 
St. Petersburg, FL 33701 
Phone: (727) 897-9000 
Fax: (727) 897-9009 
 
This study will be performed in compliance with Good Clinical Practices and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to 
the extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, 
or as required by law.  Persons to whom this information is disclosed should be informed that this 
information is confidential and may not be further disclosed without the express permission of 
VistaPharm, Inc.