Clinical trial NCT02934191
Conditions: Tonsillectomy
Keywords: Tonsillectomy Post-operative complications Post-operative pain
Sponsor: Children's Hospital of Philadelphia
Start date: 2016-06-01; Completion date: 2019-01-31
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tonsillectomy is one of the most common pediatric surgical procedures in the United States. Postoperative pain is substantial, with typical regimens employing narcotic derivatives and acetaminophen for 1-2 weeks after surgery. Recent enthusiasm for use of ibuprofen as an alternative has been tempered by equivocal data on its relative safety in regard to risk of postoperative hemorrhage. The primary objective is to evaluate efficacy of celecoxib for pain control after tonsillectomy in children. The secondary objective is to assess safety in regard to postoperative hemorrhage and adverse events.

Detailed description:
This is a randomized, double-blind, placebo-controlled trial. Subjects will take acetaminophen plus either celecoxib or placebo in regular scheduled doses, and will supplement as needed with standard of care analgesic therapy (oxycodone/acetaminophen).

Celecoxib is approved by the FDA for use in children ages 2 and older for treatment of juvenile rheumatoid arthritis (JRA). Celecoxib is on the Children's Hospital of Philadelphia (CHOP) formulary for use in (1) patients \>= 2 years old for JRA, (2) patients \>= 12 years old and \>=40 kg who have increased risk for gastrointestinal (GI) adverse effects or bleeding concerns precluding use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), and (3) oncology patients with surface area \>= 0.4 square meters for anti-angiogenesis. Celecoxib is approved by the FDA for use in adults for treatment of arthritic conditions, acute/ postoperative pain, and primary dysmenorrhea, and has been widely used since its introduction in 1998.

Setting/Participants:Subjects are healthy children aged 3 to 11 years who undergo tonsillectomy with or without adenoidectomy at any Children's Hospital of Philadelphia (CHOP) location. Subjects with coagulation disorders are excluded. Approximately 300 subjects will be enrolled, 150 in each treatment group.

Study Interventions and Measures: Subjects are provided celecoxib or placebo in scheduled doses every 12 hours for 5 days, then continue until they are pain-free, for a maximum of 10 days. Throughout the study, they are allowed to use oxycodone/acetaminophen as needed for additional pain control, following standard clinical care. Acetaminophen is used around the clock for the first 5 days in all subjects. For 14 days following surgery, subjects record pain levels on validated pain scale instruments, quantity of narcotic medication and acetaminophen required, and time to return to normal diet. All Emergency Department and hospital admissions during the 30 postoperative days are recorded, noting incidence of excess pain, dehydration, hemorrhage, and other complications.

Pain control efficacy is assessed by comparing groups for number of days in which narcotic medication was used, and total quantity of rescue pain medication consumed. Rates of hospital readmission and postoperative hemorrhage, and the need for operative control, are also compared between groups.

Arms: arm 1: Subjects will take acetaminophen orally (dose 15mg/kg/dose) in scheduled doses every 4 hours for the first 5 days. Subjects will also take celecoxib orally (dose is 6mg/kg twice a day with a maximum dose of 300mg twice a day). The first dose of celecoxib will be given preoperatively, within 1 hour prior to entering the operating room. The second dose will be given at bedtime on the night of surgery and subsequent doses will be given 12 hours apart. Supplemental standard of care oxycodone may be used to control breakthrough pain. arm 2: Subjects will take acetaminophen orally (dose 15mg/kg/dose) in scheduled doses every 4 hours for the first 5 days. Subjects will also take the placebo orally twice a day. The first dose of placebo will be given preoperatively, within 1 hour prior to entering the operating room. The second dose will be given at bedtime on the night of surgery and subsequent doses will be given 12 hours apart. Supplemental standard of care oxycodone may be used to control breakthrough pain.
Interventions: intervention 1: Celecoxib intervention 2: Placebo intervention 3: Acetaminophen intervention 4: Oxycodone
Intervention descriptions: intervention 1: Dosing will be 6mg/kg twice a day with a maximum dose of 300mg twice a day. All ages will be given the suspension (concentration 100mg/5mL) orally intervention 2: Placebo will have the same appearance, taste and consistency as celecoxib. Placebo will consist of calcium carbonate powder suspended in the same syrup as celecoxib. Dose of elemental calcium is 3 mg/kg/day. intervention 3: Acetaminophen syrup at a dose of 15mg/kg/dose will be given every 4 hours for the first 5 days after surgery. After that point, is given as needed. intervention 4: Oxycodone may be used every 4 hours post-operatively to treat breakthrough pain. The most commonly prescribed dose is 0.075mg/kg/dose (suspension) every 4 hours as needed.

Protocol documents:
Prot_SAP_000.pdf: 
 
Template version: May 28, 2014 
 
Title: 
Celecoxib for Pain Management after Tonsillectomy 
Short Title 
Celecoxib after Tonsillectomy 
Drug Name: 
celecoxib 
FDA IND 
N/A 
eIRB Number 
15-011707 
Protocol Date:   
May 12, 2015 
Amendment 1 Date:  
May 23, 2016              Amendment 3 Date: August 29, 2016 
Amendment 2 Date:           June 8, 2016 
Amendment 4 Date: October 31, 2016 
Amendment 5 Date: October 23, 2017 
 
 
Principal Investigator  
John Germiller, M.D., Ph.D. 
Division of Otolaryngology, First Floor, Wood Center 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd. 
Philadelphia, PA 19104 
 
Phone 215-590-3440  
email: germiller@email.chop.edu 
 
 
 


 
 
 
 
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms .............................................................................. v 
Abstract ................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures .............................................................................. xi 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 1 
1.3 
FINDINGS FROM CLINICAL STUDIES ..................................................................................................... 1 
1.3.1 
Clinical Studies ............................................................................................................................... 1 
1.4 
SELECTION OF DRUGS AND DOSAGES ................................................................................................... 5 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 5 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 9 
2 
STUDY OBJECTIVES .............................................................................................................................. 9 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 9 
2.2 
SECONDARY OBJECTIVES ..................................................................................................................... 9 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 10 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ............................................................................................... 10 
3.1.1 
Screening Phase ............................................................................................................................ 10 
3.1.2 
Study Treatment Phase (Postop day 0 until pain-free, maximum 10 days) ................................... 10 
3.1.3 
Follow-up Phase (Discontinuation of study drug to Postop day 30) ............................................ 12 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ...................................................................... 12 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 13 
3.3.1 
Duration of Study Participation .................................................................................................... 13 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 13 
3.4 
STUDY POPULATION ........................................................................................................................... 13 
3.4.1 
Inclusion Criteria .......................................................................................................................... 13 
3.4.2 
Exclusion Criteria ......................................................................................................................... 14 
4 
STUDY PROCEDURES .......................................................................................................................... 15 
4.1 
PRE-OP PHASE .................................................................................................................................... 15 
4.2 
STUDY TREATMENT PHASE (POSTOP DAY 0 UNTIL PAIN-FREE, MAXIMUM 10 DAYS) .......................... 15 
4.2.1 
Day of Surgery (Day 0) ................................................................................................................. 15 
4.2.2 
Telephone Call 1 (Day 3 +/- 1) ..................................................................................................... 15 
4.3 
FOLLOW-UP PHASE (DISCONTINUATION OF STUDY DRUG TO POSTOP DAY 30) ................................... 16 
4.3.1 
Telephone Call 2 (Day 14 +/- 1) ................................................................................................... 16 
4.3.2 
Telephone Call 3 (Day 30 +/- 2) ................................................................................................... 16 
4.4 
UNSCHEDULED VISITS ........................................................................................................................ 16 
4.5 
CONCOMITANT MEDICATIONS ............................................................................................................ 16 
4.6 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 17 
4.7 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 17 
4.7.1 
Early Termination Study Visit ....................................................................................................... 18 
STUDY EVALUATIONS AND MEASUREMENTS .................................................................................... 18 
4.8 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 18 
4.8.1 
Medical Record Review ................................................................................................................. 18 
4.8.2 
Laboratory Evaluations................................................................................................................. 19 
4.9 
EFFICACY EVALUATIONS ................................................................................................................... 19 


 
 
 
 
 
 
 
 
 
 
iii 
4.9.1 
Days receiving narcotic medication .............................................................................................. 19 
4.9.2 
Pain Scales (See Appendix) ........................................................................................................... 19 
4.9.3 
Measurement of Oxycodone and Acetaminophen Usage .............................................................. 19 
4.9.4 
Return to Normal Diet Assessment ................................................................................................ 20 
4.9.5 
Data Collection from Hospital Readmissions ............................................................................... 20 
4.10 
SAFETY EVALUATION ......................................................................................................................... 20 
5 
STATISTICAL CONSIDERATIONS .................................................................................................... 21 
5.1 
PRIMARY ENDPOINT ........................................................................................................................... 21 
5.2 
SECONDARY ENDPOINTS .................................................................................................................... 21 
5.3 
STATISTICAL METHODS ...................................................................................................................... 21 
5.3.1 
Baseline Data ................................................................................................................................ 21 
5.3.2 
Efficacy Analysis ........................................................................................................................... 21 
5.3.3 
Safety Analysis .............................................................................................................................. 22 
5.4 
SAMPLE SIZE AND POWER .................................................................................................................. 22 
5.5 
INTERIM SAFETY ANALYSIS ............................................................................................................... 22 
6 
STUDY MEDICATION........................................................................................................................... 24 
6.1 
DESCRIPTION ...................................................................................................................................... 24 
6.1.1 
Packaging ...................................................................................................................................... 24 
6.1.2 
Labeling ........................................................................................................................................ 24 
6.1.3 
Dosing ........................................................................................................................................... 24 
6.1.4 
Treatment Compliance and Adherence ......................................................................................... 25 
6.1.5 
Drug Accountability ...................................................................................................................... 25 
7 
SAFETY MANAGEMENT ..................................................................................................................... 26 
7.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 26 
7.2 
ADVERSE EVENT REPORTING ............................................................................................................. 26 
7.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 26 
7.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 26 
7.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 27 
7.5 
ANTICIPATED SAES ........................................................................................................................... 27 
7.6 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 28 
7.6.1 
Follow-up report ........................................................................................................................... 28 
7.7 
MEDICAL EMERGENCIES .................................................................................................................... 28 
8 
STUDY ADMINISTRATION ................................................................................................................. 30 
8.1 
TREATMENT ASSIGNMENT METHODS ................................................................................................. 30 
8.1.1 
Randomization............................................................................................................................... 30 
8.1.2 
Blinding ......................................................................................................................................... 30 
8.1.3 
Unblinding .................................................................................................................................... 30 
8.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 30 
8.3 
CONFIDENTIALITY .............................................................................................................................. 31 
8.4 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................................. 31 
8.4.1 
Data and Safety Monitoring Plan ................................................................................................. 31 
8.4.2 
Risk Assessment ............................................................................................................................. 32 
8.4.3 
Potential Benefits of Trial Participation ....................................................................................... 36 
8.4.4 
Risk-Benefit Assessment ................................................................................................................ 36 
8.5 
RECRUITMENT STRATEGY .................................................................................................................. 37 
8.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 37 
8.7 
PAYMENT TO SUBJECTS/FAMILIES ...................................................................................................... 38 
8.7.1 
Reimbursement for travel, parking and meals .............................................................................. 38 
8.7.2 
Payments to parent for time and inconvenience (i.e. compensation) ............................................ 38 
8.7.3 
Payments to subject for time, effort and inconvenience (i.e. compensation) ................................. 38 


 
 
 
 
 
 
 
 
 
 
iv
8.7.4 
Gifts ............................................................................................................................................... 39 
9 
PUBLICATION ........................................................................................................................................ 39 
10 
REFERENCES ......................................................................................................................................... 39 
Appendix ............................................................................................................................... 41 
 


 
 
 
 
 
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ACE 
Angiotensin converting enzyme 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
AUC 
Area under the curve (concentration over time) 
BID 
Twice daily 
BMI 
Body Mass Index 
CBC 
Complete blood count 
CI 
Confidence interval 
Cmax 
Peak plasma level of drug (maximum concentration) 
COX-1 
Cyclooxygenase-1 
COX-2 
Cyclooxygenase-2 
CRF 
Case report form 
CYP2C9 
Cytochrome P isozyme 2C9 
ED 
Emergency Department 
GI 
Gastrointestinal 
JIA 
Juvenile idiopathic arthritis 
JRA 
Juvenile rheumatoid arthritis 
NOS 
Not otherwise specified 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
osteoarthritis 
OR 
Odds ratio 
PACU 
Perioperative anesthesia care unit 
PK 
Pharmacokinetics 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 
SAN 
Storage area network 
SSRI 
Selective serotonin reuptake inhibitor 
T1/2 
Half life 
Tmax 
Time to peak plasma level of drug 


 
 
 
 
 
 
 
 
 
 
vi
ABSTRACT 
Context:  
Tonsillectomy is one of the most common pediatric surgical procedures in the United States.  
Postoperative pain is substantial, with typical regimens employing narcotic derivatives and 
acetaminophen for 1-2 weeks after surgery.  Recent enthusiasm for use of ibuprofen as an 
alternative has been tempered by equivocal data on its relative safety in regard to risk of 
postoperative hemorrhage.  A few centers have used celecoxib, a selective inhibitor of 
cyclooxygenase-2, which should provide pain relief without increasing bleeding risk.   
Objectives:  
The primary objective is to evaluate efficacy of celecoxib for pain control after 
tonsillectomy in children.  The secondary objective is to assess safety in regard to 
postoperative hemorrhage and adverse events. 
Study Design:  
Randomized, double-blind, placebo-controlled trial.  Subjects will take acetaminophen plus 
either celecoxib or placebo in regular scheduled doses, and will supplement as needed with 
standard of care analgesic therapy (oxycodone/acetaminophen). 
Setting/Participants: 
Subjects are healthy children aged 3 to 11 years who undergo tonsillectomy with or without 
adenoidectomy at any CHOP location.  Subjects with coagulation disorders are excluded.  
Approximately 300 subjects will be enrolled, 150 in each treatment group. 
Study Interventions and Measures:  
Subjects are provided celecoxib or placebo in scheduled doses every 12 hours for 5 days, 
then continue until they are pain-free, for a maximum of 10 days.  Throughout the study, 
they are allowed to use oxycodone/acetaminophen as needed for additional pain control, 
following standard clinical care.  Acetaminophen is used around the clock for the first 5 
days in all subjects.  For 14 days following surgery, subjects record pain levels on validated 
pain scale instruments, quantity of narcotic medication and acetaminophen required, and 
time to return to normal diet.  All Emergency Department and hospital admissions during 
the 30 postoperative days are recorded, noting incidence of excess pain, dehydration, 
hemorrhage, and other complications. 
Pain control efficacy is assessed by comparing groups for number of days in which narcotic 
medication was used, and total quantity of rescue pain medication consumed.  Rates of 
hospital readmission and postoperative hemorrhage, and the need for operative control, are 
also compared between groups. 
 


 
 
 
 
 
 
 
 
 
 
vii
PROTOCOL SYNOPSIS 
Study Title 
Celecoxib for Pain Management after Tonsillectomy  
Funder 
Pfizer and Children’s Surgical Associates 
Clinical Phase 
N/A 
Study Rationale 
Tonsillectomy is one of the most common pediatric surgical 
procedures in the United States.  Postoperative pain is substantial, 
with typical regimens employing narcotic derivatives and 
acetaminophen for 1-2 weeks after surgery.  Recent enthusiasm for 
use of ibuprofen as an alternative has been tempered by equivocal 
data on its relative safety in regard to risk of postoperative 
hemorrhage.  A few centers have used celecoxib, a selective 
inhibitor of cyclooxygenase-2, which should provide pain relief 
without increasing bleeding risk.  We aim to determine if celecoxib 
can reduce postoperative pain and narcotic usage in this population, 
without increasing risk of hemorrhage. 
Study Objective(s) 
Primary  
To measure efficacy of celecoxib for pain control after 
tonsillectomy.  The primary measures of pain control will be the 
total quantity of rescue medication consumed, and total number of 
days requiring rescue medication. 
Secondary 
• To evaluate surrogate measures of pain control, including 
time to return to normal diet, rates of pain-related 
complications and admissions (e.g., dehydration). 
• To evaluate safety in regard to rates of postoperative 
hemorrhage and adverse events. 
• To evaluate tolerability of celecoxib for short term 
administration in this population. 
Study Drug 
 
Celecoxib, as a suspension 100 mg/5mL.  Dosing is 6 mg/kg BID 
(maximum 300 mg BID). 
Study Design 
 
Randomized, double-blind, placebo-controlled trial.  Subjects will 
take acetaminophen plus either celecoxib or placebo in regular 
scheduled doses for 5 days, then continue until they are pain-free, 
for a maximum of 10 days.  They will supplement as needed with 
standard of care analgesic therapy (oxycodone/acetaminophen).   
Subject Population 
Inclusion Criteria 
1. Males and females age 3 to 11 years inclusive.   


 
 
 
 
 
 
 
 
 
 
viii
key criteria for 
Inclusion and 
Exclusion: 
 
 
2. Scheduled to undergo tonsillectomy (with or without 
adenoidectomy). 
3. Weight ≥ 10 kg. 
4. Girls ≥ 11 years of age must have a negative urine/serum 
pregnancy test on the day of surgery and must use an 
acceptable method of contraception, including abstinence, a 
barrier method (diaphragm or condom), Depo-Provera, or an 
oral contraceptive, for the duration of the study. 
5. Parental/guardian permission (informed consent) and if 
appropriate, child assent. 
Exclusion Criteria 
1. Prior tonsillar surgery. 
2. Concomitant surgical procedure that adds more than mild 
additional pain.  Note: ear tubes are always permissible. 
3. Coagulation disorder, or any other hematologic disorder that 
affects clotting or results in anemia. 
4. Moderate to severe asthma, defined as subjects who either 
(1) have daily symptoms requiring daily use of short-acting 
bronchodilators, or (2) had an exacerbation in the last 3 
months requiring admission, ED visit, or systemic 
corticosteroid administration. 
5. Any degree of aspirin-sensitive asthma, or any history of 
asthma exacerbation caused by NSAID use. 
6. Severe obstructive sleep apnea that requires use of CPAP or 
BiPAP. 
7. Significant chronic pulmonary disease, defined as subjects 
requiring oxygen therapy, ventilator support, or positive 
pressure therapy. 
8. Significant cardiac disease, defined as any one of the 
following: cardiovascular disease, structural cardiac 
anomalies, prior cardiac surgery, or requirement for cardiac 
anesthesia.   
9. Severely obese (BMI > 99th percentile for age). 
10. History of hepatic or renal disease, or condition that impairs 
hepatic or renal function. 
11. Juvenile rheumatoid arthritis (JRA). 
12. History of GI bleeding, or chronic GI condition that would 
increase risk of bleeding, ulceration, or perforation. 


 
 
 
 
 
 
 
 
 
 
ix
13. Hypertension.  
14. Craniofacial syndromes. 
15. Syndrome or neurologic condition that would hinder 
accurate assessment of postoperative pain. 
16. Inability to feed orally or take oral pain medication. 
17. Chronic pain disorders, or otherwise requiring pain 
medication more than once weekly. 
18. Laboratory abnormalities on the preoperative CBC: 
Hemoglobin  
< 9 gm/dL 
Platelet count 
< 100,000/mm3 
19. Any investigational drug use within 30 days prior to 
enrollment.  
20. Pregnant or lactating females.  
21. Parents/guardians or subjects who, in the opinion of the 
Investigator, may be non-compliant with study schedules or 
procedures. 
22.  Hypersensitivity or allergic reactions to celecoxib, aspirin, 
or other NSAIDs, including asthma flare ups. 
23. Allergy to sulfonamides or calcium carbonate. 
Number Of Subjects  
 
Total 300 subjects, equally divided between celecoxib and placebo. 
Study Duration 
Each subject’s participation will last from 1-4 months. 
The entire study is expected to last 1 year. 
Study Phases 
    
(1) Screening: screening for eligibility and consent obtained.  This 
is done at the pre-operative office visit. 
(2) Study Drug Treatment: After surgery, subjects consume study 
medication every 12 hours for 5 days, then until pain-free, for a 
maximum 10 days. 
(3) Follow-Up: Admissions to ED or hospital are recorded during 
the 30 postoperative days.  Subjects receive telephone follow up 
at 3, 14, and 30 days to assess compliance and record any 
complications or AEs  
Efficacy Evaluations 
 
 
Pain control efficacy is assessed by comparing number of days in 
which narcotic medication was used, and total quantity of rescue 
pain medication consumed.  Also compared are time to return to 


 
 
 
 
 
 
 
 
 
 
x
normal diet, and rates of ED or hospital readmission for dehydration 
and excessive pain. 
Safety Evaluations 
Recording of AEs and comparison of celecoxib to placebo groups.  
Rates of hospital readmission and postoperative hemorrhage, and 
the need for operative control, will also be compared between 
groups. 
Statistical And 
Analytic Plan 
Primary efficacy endpoints are number of days requiring rescue 
narcotic medication, and total amount of rescue narcotic consumed, 
expressed as morphine equivalents and normalized to body weight.  
Secondary efficacy endpoints are the time to return to normal diet, 
and rate of readmission for dehydration or excessive pain.  These 
are compared between celecoxib and control groups using two-
sample t-tests.   
The primary safety endpoints are rates of AEs and rates of 
postoperative hemorrhage.  These will be compared by descriptive 
summaries. 
DATA AND SAFETY 
MONITORING PLAN 
The P.I. will be responsible for monitoring the integrity of the data 
and the safety of all subjects.   The PI reviews SAEs immediately, 
and other AEs during regular meetings with the study team 
approximately every 2 weeks.  Data is collected for all hospital 
readmissions in the 30 days following surgery, and this includes the 
AE data.   AEs are reported to the IRB as described in the protocol 
section AE Reporting.  There is no Data Safety Monitoring Board 
for this study. 
 


 
xi  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Treatment 
Follow-up 
Visit / Activity 
Before 
Surgery  
Surgery 
Day 
Treatment 
(home) 
Call 1 
Treatment 
(home) 
Home 
Observation 
Call 2 
Call 3 
Postoperative Day 
 
0 
1-5 
3(+/-1) 
6-10 
11-14 
14(+/-1) 
30 (+/-2) 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
Physical Examination 
X1 
 
 
 
 
 
 
 
Vital Signs: BP, HR, RR 
 
X2 
 
 
 
 
 
 
Height and Weight 
X1 
 
 
 
 
 
 
 
Pregnancy Test 
 
X2 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X1 
X2 
 
 
 
 
 
 
CBC with platelets  
X1 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
 
 
 
 
 
Administer Study Drug 
 
X 
X 
X 
X3  
 
 
 
Acetaminophen 
 
X 
X 
X 
PRN 
PRN 
 
 
Oxycodone 
 
PRN 
PRN 
PRN 
PRN 
PRN 
 
 
Diary- Pain, Narcotic use, 
diet, fluid intake, urine output 
 
X 
X 
X 
X 
X 
 
 
Drug compliance 
 
 
 
X 
 
 
X 
 
Drug accountability 
 
 
 
 
 
 
X 
 
Adverse Event Assessment 
 
 
 
X4 
 
 
X 
X 


 
xii  
 
 
 
 
 
 
 
 
Notes 
1- 
These are clinical care; they are recorded from the preoperative office visit. 
2- 
Recorded from perioperative records.  Pregnancy testing for females of childbearing potential is always done as part of clinical care before surgery in the 
preoperative area. 
3- 
Duration of study drug is until child is pain-free (see text), or the maximum of 10 days has been reached. 
4- 
Includes specific query about skin rash.   If skin rash has occurred, subjects discontinue study medication.


 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Tonsillectomy is one of the most common pediatric surgical procedures in the United States.  
Postoperative pain is substantial, with typical regimens employing narcotic derivatives and 
acetaminophen for 1-2 weeks after surgery.  Ibuprofen has been used by some centers as an 
alternative to narcotics, and has proven effective for pain control.  However, ibuprofen 
inhibits platelet function, and the possibility that it might increase risk of postoperative 
bleeding, combined with equivocal data regarding its safety, has limited its widespread 
adoption in this setting.  Tonsillectomy carries a significant bleeding risk of 2-5%, and 
hemorrhage events are often emergent situations, since they typically occur 1-2 weeks after 
surgery when patients are at home. Up to half of patients who have hemorrhage require re-
operation.   
A few centers have used celecoxib to control post-tonsillectomy pain.  Celecoxib is a newer 
nonsteroidal anti-inflammatory drug (NSAID) that is a selective inhibitor of 
cyclooxygenase-2. Because platelet inhibition is mediated via cyclooxygenase-1, celecoxib 
should provide pain relief without increasing bleeding risk like traditional NSAIDs.  We 
hope to employ this drug as a key element in post-tonsillectomy management, and this study 
represents the first step in evaluating its efficacy and safety. Specifically, we aim to 
determine if celecoxib can reduce postoperative pain and narcotic usage after tonsillectomy, 
without increasing risk of hemorrhage.  
1.2 Name and Description of Investigational Product or Intervention 
The study drug is celecoxib. Celecoxib is a nonsteroidal anti-inflammatory drug with anti-
inflammatory, analgesic, and antipyretic activities. Its mechanism of action is by inhibition 
of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at 
therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase-1 
(COX-1) isoenzyme.  
Celecoxib is approved by the FDA for use in children ages 2 and older for treatment of 
juvenile rheumatoid arthritis.  Celecoxib is on the CHOP formulary for use in (1) patients >= 
2 years old for JRA, (2) patients >= 12 years old and >=40 kg who have increased risk for 
GI adverse effects or bleeding concerns precluding use of traditional NSAIDs, and (3) 
oncology patients with surface area >= 0.4 square meters for anti-angiogenesis.  Celecoxib is 
approved by the FDA for use in adults for treatment of arthritic conditions, acute/ 
postoperative pain, and primary dysmenorrhea, and has been widely used since its 
introduction in 1998. 
1.3 Findings from Clinical Studies  
1.3.1 Clinical Studies 
1.3.1.1 Human Pharmacokinetics 
The following are adapted from the Full Prescribing Information for Celebrex (Pfizer, Inc). 
 


 
  
 
 
 
2
Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. 
Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) 
are roughly dose-proportional up to 200 mg BID; at higher doses there are less than 
proportional increases in Cmax and AUC.  Absolute bioavailability studies have not been 
conducted.  With multiple dosing, steady-state conditions are reached on or before Day 5. 
The pharmacokinetic parameters of celecoxib in a group of healthy adult subjects are shown 
in Table 2 below.  
 
Table 2 : Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in 
Healthy Adult Subjects  
 
 
 Subjects under fasting conditions (n=36, 19-52 
yrs.) 
 
 
 
Kinetics of suspension formulation and sprinkled capsules:  In healthy adult volunteers, the 
overall systemic exposure (AUC) and Cmax of celecoxib was equivalent when celecoxib was 
administered as an intact capsule, as capsule contents sprinkled on applesauce, or as a 20 
mg/mL oral suspension. There were no significant alterations in Cmax, Tmax or t1/2 after 
administration of capsule contents on applesauce [Krishnaswami et al 2012].   
Distribution: In healthy subjects, celecoxib is highly protein bound (~97%) within the 
clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to 
a lesser extent, α1-acid glycoprotein.  The apparent volume of distribution at steady state 
(Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues.   
Metabolism: Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a 
primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been 
identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.  
Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) 
unchanged drug recovered in the urine and feces. Following a single oral dose of 
radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was 
excreted into the urine. The primary metabolite in both urine and feces was the carboxylic 
acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the 
urine. It appears that the low solubility of the drug prolongs the absorption process making 
terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 
11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 
mL/min.   
Pediatric Pharmacokinetics:  
Single-dose and steady-state pharmacokinetics were investigated in 10 children aged 6-16 
receiving celecoxib over a 1 week period for anti-angiogenesis [Stempak et al 2002].  The 
drug was absorbed and distributed similarly as adults, but was metabolized much faster.  
Mean (%CV) PK Parameter Values 
Cmax, ng/mL Tmax, hr Effective t1/2, hr Vss/F, L CL/F, L/hr
705 (38) 
2.8 (37) 
11.2 (31) 
429 (34) 27.7 (28) 


 
  
 
 
 
3
Celecoxib was cleared approximately twice as fast as adults, and had a half-life 
approximately half as long (3.7 hours compared to 8.9 hours).  These findings led the 
authors to conclude that higher or more frequent dosing may be needed in children, rather 
than simply the use of weight-adjusted adult dosing. 
The steady state pharmacokinetics of celecoxib administered as an investigational oral 
suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg 
with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA.  
Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body 
weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 
25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with 
a 70 kg adult RA patient.  Based on these data, the manufacturer recommends twice-daily 
administration of 50 mg capsules to JRA patients weighing ≥10 to ≤25 kg and 100 mg 
capsules to JRA patients weighing >25 kg to achieve plasma concentrations similar to those 
observed in a clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 
(see Clinical Studies in Children, below). Celecoxib has not been studied in JRA patients 
under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 
weeks duration of therapy.   
Platelet pharmacodynamics: In clinical trials using normal volunteers, celecoxib at single 
doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration 
(higher than recommended therapeutic doses) had no effect on reduction of platelet 
aggregation or increase in bleeding time.  
1.3.1.2 Clinical Studies in Adults 
Celecoxib has been well studied in adults and is widely used in the management of 
rheumatoid arthritis and osteoarthritis (OA).  In knee and hip OA, celecoxib was evaluated 
in placebo- and active-controlled clinical trials of up to 12 weeks duration. Treatment with 
celecoxib 100 mg twice daily or 200 mg once daily resulted in improvement in pain, 
stiffness, and functional measures in OA.  In three 12-week studies of pain accompanying 
OA flare, celecoxib doses of 100 mg twice daily and 200 mg twice daily provided 
significant reduction of pain within 24-48 hours of initiation of dosing [Celebrex Full 
Prescribing Information, Pfizer Inc.]  
Celecoxib has also been studied in adults for managing acute pain after surgery, and in 
primary dysmenorrhea.  In acute analgesic models of post-oral surgery pain, post-orthopedic 
surgical pain, and primary dysmenorrhea, celecoxib relieved pain that was rated by patients 
as moderate to severe.  Single doses provided pain relief within 60 minutes. [Celebrex Full 
Prescribing Information, Pfizer Inc.]  Li et al [2009] studied 51 adults over 55 years of age 
receiving total hip replacement, randomized to diclofenac, rofecoxib, or placebo.  Overall, 
ADRs were similar between the two NSAIDs.  Rofecoxib resulted in less perioperative 
blood loss compared to diclofenac (7% increase over placebo with rofecoxib, vs. 32% 
increase over placebo with diclofenac). 
Adverse drug reactions (ADRs) of celecoxib appear to be similar to other NSAIDs.  Upper 
GI bleeding is a known risk of chronic NSAID therapy.  In a large population-based, nested 
case-control analysis of 10,892 adults, Hippisley-Cox et al [2005] studied rates of first-ever 


 
  
 
 
 
4
adverse upper GI events.  The COX-2 inhibitors (rofecoxib or celecoxib) were found 
comparable to the traditional NSAIDs (ibuprofen, diclofenac, and naproxen).  For further 
discussion of adverse reactions, see Section 9.4 below.   
Adverse Events from the analgesia and dysmenorrhea studies: Approximately 1,700 
patients were treated with celecoxib in studies of post-oral surgery pain (single dose), and of 
analgesia and dysmenorrhea (up to 600 mg/day). The types of adverse events were similar to 
those reported in arthritis studies. The only additional adverse event reported was post-
dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. For 
further discussion of adverse reactions, see Section 9.4 below.   
1.3.1.3 Clinical Studies in Children 
Celecoxib has been studied in children, mainly with juvenile rheumatoid arthritis, and was 
found to be effective and well tolerated.  Foeldvari et al [2009] studied celecoxib at 2 dose 
levels in 242 children aged 2-17 years, at least 9 kg, compared to naproxen, for 12 weeks, 
with a 12-week open label extension.  The drug was given as a suspension (10 mg/mL or 20 
mg/mL for the low and high-dose groups, respectively). Celecoxib was non-inferior to 
naproxen for efficacy, and safety data (adverse events) were comparable between groups.  
This was true even with fairly high dosages in the high-dose group -- 6 mg/kg BID 
(maximum of 300 mg BID). The most common (>5%) adverse events were headache, fever, 
upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea 
and vomiting. Similar AEs and rates were seen in the naproxen-treated subjects.   The 
incidence of AEs in the 12-week, open-label extension was similar during the double blind 
study, and this was at the higher celecoxib dose (6 mg/kg BID).   
Murto et al [2015] studied celecoxib in 282 children age 2-18 who underwent tonsillectomy.  
This study used a loading dose of 6 mg/kg preoperatively followed by 3 mg/kg BID on 
postoperative days 0-2.  The drug was given as a suspension (10 mg/mL). Celecoxib was 
effective for pain reduction and was well-tolerated, with no difference in adverse events 
between the celecoxib and placebo groups.  The results are detailed further in Section 1.5, 
“Use after tonsillectomy,” below.   
Sobel et al [2014] compared safety of celecoxib and ibuprofen from a Phase-4 registry in 
274 children 2-17 years with JIA/JRA.  Again, adverse drug reactions (ADRs) were 
comparable; no bleeding events were reported.  In a retrospective review of ADRs, Titchen 
et al [2005] compared several NSAIDs in 19 children who had ADR reports between 1999 
and 2003.  Again total AEs were comparable among celecoxib, rofecoxib, and the standard 
NSAIDs.  Finally in a Cochrane Review, Derry et al [2013] report 1785 children and adults 
15 years and older, receiving a single dose of celecoxib vs placebo for moderate to severe 
postoperative pain.  Celecoxib was effective in pain reduction, and AEs were generally mild 
to moderate in severity, and were experienced by a similar proportion of participants in the 
celecoxib and placebo groups.  
In summary, celecoxib has been shown safe and effective in children receiving short term 
therapy, much longer than that proposed in the present study.   Its efficacy and safety 
however have not been studied beyond six months of treatment.   
  


 
  
 
 
 
5
1.4 Selection of Drugs and Dosages 
Celecoxib is available commercially only as capsules.  In young children, it is typically 
administered by opening the capsules and sprinkling the drug on puree food such as 
applesauce.  Older children may swallow capsules whole if they are capable. 
Suspension formulations have been used in several large studies in children.  The trials in 
children with both JRA and tonsillectomy, detailed above, used suspensions of 10 or 20 
mg/mL made at the local institutions [Foeldvari et al 2009, Murto et al 2015]. The 
suspensions are stable at least 93 days at either room temperature or refrigerated [Donnelly 
et al 2009].  Pharmacokinetic analysis has been performed in both adults and children 
[Krishnaswami et al 2012], showing drug bioavailability in the suspensions that was 
equivalent to capsule or sprinkle administration. 
Dosage endorsed by the FDA for children with JRA is 50 mg BID for weight 10 kg to <=25 
kg, and 100 mg BID for weight >25 kg.  This is approximately 3 mg/kg BID, which was the 
dose used in the recent pediatric tonsillectomy trial by Murto et al [2015], and was also the 
lower dose group in the pediatric JRA trial [Foeldvari 2009].  However, the conclusion of 
the Murto group was that this dose is too low to produce major relief of the acute pain after 
tonsillectomy.  Citing the PK study by Stempak [2002] showing shorter half life and more 
rapid clearance in children, the authors recommended higher dosing for tonsillectomy and a 
longer duration of therapy.   
Indeed, much higher doses have been well tolerated in children.  As noted earlier, the higher 
dose group in the Foeldvari study (6 mg/kg BID) had rates of adverse events comparable to 
the lower dose group, even when given well over 12 weeks.  Furthermore, the PK study by 
Stempak et al [2002] used even higher doses (average 8.6 mg/kg BID, range 7-12 mg/kg 
BID) for over one week in 10 cancer patients aged 6-16, with no reported toxicity.  
Based on data from all the studies in children, our dosing for the present study is as follows. 
Children will receive 6 mg/kg BID (maximum 300 mg BID) for the duration of their acute 
pain, up to a maximum of 10 days.  We will formulate study drug into a suspension 
following the method of Donnelly et al [2009], except with a 20 mg/mL concentration to 
facilitate the current dosing.  The latter concentration was used effectively in the JRA trial as 
well.  Subjects will receive their first dose just before surgery, following Murto et al [2015]. 
 
1.5 Relevant Literature and Data 
Background 
Pain management after pediatric adenotonsillectomy remains a significant health care 
problem [Baugh et al, AAO-HNSF Clinical Practice Guideline, 2011].   Historically, pain 
has been managed with opiates, but recently there has been increased interest in reducing the 
use of opiates in children, particularly following the recent FDA black-box warning that 
followed reports of deaths in children treated with codeine after tonsillectomy, who had an 
uncommon genetic variant causing hypermetabolism of codeine [Kuehn 2013].    


 
  
 
 
 
6
Accordingly, there has been increased interest in use of non-narcotic alternatives, including 
NSAIDs, for postoperative tonsillectomy pain management.  Many centers use NSAIDs 
extensively for pain management.  However, because this surgery is notable for a significant 
risk of life-threatening airway hemorrhage of 2-5%, there has been reluctance nationally to 
adopt widespread use of NSAIDs for this indication, based on the tendency of traditional 
nonselective NSAIDs to inhibit platelet function, and thus possibly increase bleeding risk. 
At this time, the literature remains equivocal about the safety of traditional NSAIDs 
regarding postoperative bleeding risk.  In a 2011 Practice Guideline published by the 
American Academy of Otolaryngology-Head & Neck Surgery, conflicting evidence was 
presented.  A Cochrane review of 13 randomized trials involving 955 children requiring 
surgical intervention for bleeding, and 7 trials involving 471 children not requiring surgical 
intervention, found that NSAIDs did not significantly increase bleeding risk [Cardwell et al 
2005]. Furthermore, a meta-analysis found increased risk from use of aspirin, but not for 
nonaspirin NSAIDs such as diclofenac and ibuprofen [Krishna et al, 2003].  On the other 
hand, another systematic review found some evidence for increased risk of reoperation for 
bleeding in patients given NSAIDs postoperatively [Møiniche et al 2003].    
Importantly, since that publication, an updated Cochrane review was published [Lewis et al, 
2013]. There were 15 studies involving 1101 children in this updated review.  Fourteen 
studies compared NSAIDs with other analgesics or placebo and reported on bleeding 
requiring surgical intervention. The use of NSAIDs was associated with a nonsignificant 
increase in the risk of bleeding requiring surgical intervention: Peto odds ratio (OR) 1.69 
(95% confidence interval (CI) 0.71 to 4.01). In 10 studies involving 365 children, NSAIDs 
did not significantly alter the number of perioperative bleeding events requiring non-surgical 
intervention: Peto OR 0.99 (95% CI 0.41 to 2.40), but the confidence intervals did not 
exclude an increased risk.  The Cochrane group concluded that “there is insufficient 
evidence to exclude an increased risk of bleeding when NSAIDs are used in paediatric 
tonsillectomy”[Lewis et al, 2013]. 
CHOP experience with NSAIDs post-tonsillectomy 
For approximately 1 year, CHOP Otolaryngology used ibuprofen extensively an adjunct to 
pain management for tonsillectomy patients.  Though primary pain management remained 
acetaminophen and oxycodone, patients were instructed to add the ibuprofen if they 
experienced breakthough pain.   Ibuprofen was also commonly used in-house, in younger 
patients admitted postoperatively for observation.  Indeed, it was quite successful as a rescue 
medication, with successful resolution of pain escalations requiring calls to phone triage, as 
well as significant reduction in pain calls overall (unpublished internal review, summer 
2013).  However, a possible rise in overall rates of postoperative hemorrhage was observed 
during the ibuprofen period, and also in rates of bleeding requiring re-operation.   In a 4 
month period reviewing 696 tonsillectomy cases, overall events were 33/696 = 4.7%, 
including 20 (3.5%) requiring re-operation (unpublished internal review, Spring 2014).  
These were slightly increased over historical rates in our Division of about 3-4% and 2%, 
respectively.  Importantly, during that time ibuprofen status of each individual patient was 
not documented, so it is unclear how many of these cases were actually using rescue 


 
  
 
 
 
7
ibuprofen at home.   Nevertheless, it was clear that an increase trend toward hemorrhage was 
evident during the time ibuprofen was most extensively used. 
More recently, in the Spring of 2014, there were 3 notable severe hemorrhage events in 
which ibuprofen was known to have been used.  Two lost significant blood volume and were 
difficult to control in the operating room and required transfusions, which are rarely needed 
in this situation.  The third child had hemorrhage severe enough to require tracheotomy.  
These 3 severe events prompted our Division Chief to suspend the use of ibuprofen 
throughout the Division.  The prevailing opinion in our Division at this time is that 
ibuprofen slightly increases overall bleeding risk, but more importantly, it increases the 
severity of the events when they do occur.  This has prompted our division as a group to 
seek a safer alternative to ibuprofen for pain management. 
Current CHOP Standard of Care for Pain Management 
Standard care at CHOP is oxycodone (0.075 mg/kg/dose) and acetaminophen (15 
mg/kg/dose), as liquid formulations for all ages.  Both are officially prescribed as every 4 
hours as needed, but patients are usually instructed by the PACU nurses to use the 
acetaminophen and oxycodone around the clock for the first few days, until their pain 
becomes less intense.  The number of days are not specified.  Patients then switch to using 
both as-needed.  The only patients not routinely advised to use around-the-clock dosing are 
the very young infants and toddlers (under age 3).  
Patients are instructed to call the phone triage nurses if they experience uncontrolled pain at 
home.  In that case, the phone triage nurse first confirms the patient is taking their 
acetaminophen and oxycodone.  Their oxycodone dose is then increased as necessary up to 
0.1 mg/kg/dose every 4 hours, with referral to the ED if pain is still not controlled.  Review 
of phone triage logs revealed over 24% of patients called with pain issues, and 7-8% 
required up-dosing of oxycodone (Internal QI data, March 2013). 
Celecoxib as a possibly safer alternative 
Celecoxib is a selective inhibitor of cyclooxygenase-2.  As such, it provides the pain control 
of traditional, nonselective NSAIDs, but without their side effect of platelet inhibition, 
which is mediated through COX-1.  Celecoxib is widely used in the management of pain of 
rheumatoid arthritis and osteoarthritis in adults, and is FDA-approved in children 2 years 
and older and > 10 kg for management of juvenile rheumatoid arthritis (see Clinical Studies, 
above).   It is currently on the CHOP Formulary for this indication.   
Use after tonsillectomy 
There is limited data on use of Cox-2 inhibitors after surgery in children, including 
tonsillectomy.   Before it was withdrawn from the market, another Cox-2 inhibitor, 
rofecoxib, was administered to children successfully with no increase in bleeding rates 
observed [Joshi et al 2003].  Rofecoxib, which was available as a liquid formulation, was 


 
  
 
 
 
8
pulled from the market in 2004 over concerns for increased risk of myocardial infarction in 
adults with coronary artery disease. 
In adults, several small studies found celecoxib to be safe and effective after tonsillectomy.  
A small study of 120 adults in Finland compared celecoxib capsules to ketoprofen, a 
nonselective NSAID, after tonsillectomy.  While ketoprofen provided a better initial pain 
control, after discharge, recovery with celecoxib was faster and the rate of secondary 
hemorrhage was lower (<1%,  vs. 6% with ketoprofen) [Nikanne et al 2005].   The 
University of Iowa also reported a small study of celecoxib capsules after tonsillectomy in 
adults (N=18, randomized, placebo-controlled).  In this small cohort, celecoxib reduced 
postoperative narcotic and acetaminophen requirements compared to placebo; no 
postoperative hemorrhages were noted in either group. [Van Daele et al, 2014] 
Celecoxib itself has not yet been widely used for pediatric tonsillectomy, likely due to the 
fact that a liquid formulation is not yet commercially available.  The Children’s Hospital of 
Eastern Ontario developed their own oral suspension, which it now uses it as its primary 
regimen for pain control (S. Kherani MD, personal communication).   The suspension is 
stable for 90 days and its details were published [Donnelly et al, 2009].   
The CHEO group recently completed a randomized trial comparing celecoxib to placebo in 
282 children after tonsillectomy [Murto et al, 2015].  Celecoxib was given as a loading dose 
of 6 mg/kg just prior to surgery, followed by 3 mg/kg BID for 5 more doses.  They used 
their in-house suspension of 10 mg/mL referenced above.  The 3 mg/kg dose was chosen as 
it closely approximates that recommended for children with JRA.  Pain scores were found to 
be significantly lower in the celecoxib group, though the reductions were only modest (11% 
reduction in worst pain levels for postoperative days 0-2).  Co-analgesic consumption was 
also modestly but significantly reduced (20% less consumption of acetaminophen and oral 
morphine).  Notably, the dosing period was very short (2 days), after which pain scores 
rebounded to levels equal to or greater than placebo, for the duration of the postoperative 
recovery.  In this trial, celecoxib was found safe and well tolerated, with rates of adverse 
events, including bleeding, no different from placebo. 
Of interest, the group separately analyzed the data from the 7.4% of their cohort who were 
genetically slow metabolizers of celecoxib (CYP2C9*3 heterozygotes).  Children in this 
subgroup receiving celecoxib showed greater relief of pain, and for a longer duration, than 
those with the normal genotype.   
In summary, the authors found: (1) only modest pain reduction, followed by immediate 
rebound, when children were given standard celecoxib dosing (which was developed based 
on JRA patients); (2) an excellent safety profile; (3) better pain control in the slow 
metabolizers.  These findings, combined with prior data showing celecoxib to have more 
rapid clearance in children compared to adults [Stempak 2002, detailed above], led the 
authors to conclude that different doses should be used after tonsillectomy.  They 
recommended a higher dose of the drug, and for longer duration, to ensure more effective 
pain control in this setting.  Finally, noting the synergy of acetaminophen with NSAIDs, 


 
  
 
 
 
9
they also recommended adding supplemental acetaminophen “around the clock,” as the 
combination may provide greater analgesic effects.  
Summary of current evidence and rationale  
The available evidence regarding safety of ibuprofen after tonsillectomy remains equivocal, 
even after several systematic reviews and meta-analyses.  Additionally, CHOP 
Otolaryngology has clinically observed increased severity of bleeding events in patients who 
received ibuprofen.   These observations support the search for a safer alternative for pain 
management.  The ideal drug would decrease narcotic usage in children, while not 
increasing bleeding rates over traditional regimens (narcotic+ acetaminophen), be well-
tolerated, and have experience in its use in children.  Celecoxib satisfies these criteria, with 
enough preliminary data to suggest it is effective for pain control while not increasing 
bleeding risk.  Furthermore, recent pediatric data confirm it is safe and effective after 
pediatric tonsillectomy, and confirm the efficacy and safety of an oral suspension.  
However, the fact that benefits were only modest under the current approved dosing for 
chronic use in JRA, suggests that higher doses are needed in children undergoing this 
surgical procedure.  This the rationale for the doses used the present study. 
1.6 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations and the Good Clinical Practice: Consolidated Guideline approved by the 
International Conference on Harmonisation (ICH). All episodes of noncompliance will be 
documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to determine the efficacy and safety of celecoxib when used for 
pain control after tonsillectomy. 
2.1 Primary Objective 
The primary objective of this study is to determine whether celecoxib reduces pain in 
children 3 to 11 years after tonsillectomy.  The primary measures of pain control will be 
total quantity of rescue pain medication used, and number of days on rescue medication. 
2.2 Secondary Objectives 
The secondary objectives are to: 


 
  
 
 
 
10 
• Determine whether celecoxib shortens time to return to normal diet.   
• Determine whether celecoxib reduces pain-related complications and readmissions (e.g. 
admissions for dehydration, calls or ED admissions for excessive pain). 
• Determine whether celecoxib increases rate of post-tonsillectomy hemorrhage compared 
to placebo. 
• Evaluate the tolerability of celecoxib for short-term administration after tonsillectomy. 
• Evaluate safety in terms of rates of other adverse events. 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This is a randomized, double-blind, placebo-controlled trial.  Subjects will take either 
celecoxib or placebo in regular scheduled doses, twice daily for a maximum of 10 days 
following tonsillectomy surgery, and will supplement as needed with standard of care 
analgesic therapy (oxycodone/acetaminophen).  Subjects record pain scores, narcotic 
consumption, and type of diet daily for 14 days.  Follow up telephone calls are performed by 
registered nurses during therapy, and by study staff the end of the recovery period (2 weeks), 
and at 30 days.  Adverse events, admissions, and complications are recorded during follow 
up calls, from patient diaries, and from hospital records.  The overall schema is presented in 
the Table of Study Procedures above. 
3.1.1 Screening Phase 
Potential subjects are identified during the pre-operative office visit by the physicians and 
nurse practitioners in the Division of Otolaryngology.  Subjects will have been already been 
determined to need tonsillectomy surgery, with or without adenoidectomy, will have been 
consented for the surgical procedure, will have just undergone the preoperative anesthesia 
pre-visit process, which includes history and physical, and assessment of comorbid 
conditions that affect surgery.  Potential subjects are screened for inclusion and exclusion 
criteria, then the study is explained, including the randomization scheme, risks, benefits, and 
alternatives, then subjects are approached for informed consent/ assent.  Subjects who 
consent/assent to the study are randomized to either study drug or placebo prior to surgery. 
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study-related procedures being performed.  Note that blood samples 
(CBC with platelets) are drawn on all subjects as part of clinical care, and all females of 
childbearing potential undergo a preoperative urine pregnancy test on the day of surgery, 
also as clinical care. 
3.1.2 Study Treatment Phase (Postop day 0 until pain-free, maximum 10 days) 
This Phase includes the day of surgery (Day 0), and up to 10 postoperative days, during 
which time subjects receive study medication.  
Subjects receive their first dose of study medication just before surgery in the preoperative 
holding area. After surgery, subjects undergo usual clinical care in the post-anesthesia care 


 
  
 
 
 
11 
unit, then are either discharged to home (Day Surgery), or are admitted for inpatient 
observation as per clinical care.  The procedures below are identical for either pathway.   
They then receive a dose of study drug that evening, then twice daily thereafter, at 12 hour 
intervals.  Pain levels are assessed just before each dose of study medication, and as needed 
in between. All subjects take acetaminophen (15 mg/kg/dose) in scheduled doses every 4 
hours for the first 5 days.  During those 5 days, any acetaminophen dose scheduled during 
the early morning hours (midnight to 6 AM) will be optional if subject is asleep. After 5 
days, acetaminophen is taken as needed.   
Subjects supplement with standard of care oxycodone to control any breakthrough pain.  
Subjects record volume of oxycodone consumed throughout the 2-week recovery period, the 
pain scores, and time to return to normal diet.  A follow up call by a study nurse occurs at 
Day 3 (+/- 1 day) to assess compliance with medication, pain control, compliance with 
symptom diaries, and adverse events.   
During this phase, subjects take study medication for 5 days, then continue until the point 
they are pain-free, defined as follows:  At the time a dose of study drug is due, the subject’s 
pain score is now 0, and has also been 0 for the last 24 hours (total 3 consecutive ‘0’ scores), 
AND the subject has not required any rescue medication in prior 24 hours.  The maximum 
duration on study medication is 10 days.  Based on clinical experience, we expect most 
subjects will require pain medication about 8 days [Sobol et al, 2006]. 
Before discharge, as per clinical care, subjects receive specific instructions to call the 
emergency line if they experience any hemorrhage, even in small amounts.  In addition, 
subjects are instructed to discontinue study medication if they experience either skin rash or 
hemorrhage.  These, or any other complications occurring during the treatment and follow 
up periods (e.g., dehydration), are managed according to usual clinical care pathways, 
including referral to the ED as appropriate.  There are no changes to these pathways related 
to the study.   However, the occurrence and outcomes of such complications are recorded for 
study purposes. 
During the treatment period, subjects self-monitor for dehydration, and are treated and/or 
readmitted as per clinical judgement, which is all standard of care.  This includes specific 
recording of fluid intake and number of voids each day in the Study Diary.  Additionally, 
these are assessed by the nurse on the Day 3 telephone call.  Subjects with low urine output 
(less than 1 void every 12 hours), inadequate oral intake (based on weight), or other clinical 
concern for dehydration are referred to the ED.  Evaluation and management then follow 
established pathways (http://www.chop.edu/clinical-pathway/gastroenteritis-and-
dehydration-clinical-pathway).  Subjects judged to have significant dehydration receive IV 
fluid rehydration and evaluation of serum electrolytes; BUN and creatinine are also assessed 
per clinical judgement.  All subjects whose dehydration is serious enough to require IV 
fluids, or who have abnormal serum creatinine (>1.5X upper limit of normal for age), will 
discontinue the study drug for the duration of the study.  Any abnormalities of electrolytes 
or renal function will be reassessed as per clinical care. These results are all recorded by the 
study team. Subjects not requiring IV fluids or lab draws in the ED will be considered as 
mild dehydration and will continue the study medication, once they demonstrate adequate 


 
  
 
 
 
12 
oral intake.  The above procedures will apply whether the subject is seen at CHOP or at an 
outside emergency department. 
The rationale for the 5 day minimum dosing is as follows.  First, all subjects are expected to 
have pain lasting at least 5 days.  Second, while celecoxib has effects within hours, it may 
take up to 5 days for subjects to reach their final steady-state levels of pain control (as 
discussed in section 1.3.1.1).  Third, by the same logic, 5 days would also be the minimum 
time to know the side effect profile of the drug.  Fourth, a 5 day minimum would reduce the 
risk of pain relapse in the active drug group.   If celecoxib turns out to be extremely effective 
for pain, subjects could become pain-free well before their tonsillectomy wounds have 
healed.  Without a 5 day minimum, these subjects would discontinue study drug too early, 
and would likely relapse into an undesirable state of uncontrolled pain.  
3.1.3 Follow-up Phase (Discontinuation of study drug to Postop day 30) 
In clinical practice at CHOP and at most centers, patients do not generally return for 
postoperative follow up visit after tonsillectomy surgery.  This will be the case for subjects 
in this study as well, with all routine follow up conducted by telephone contact, without any 
further scheduled Study Visits.  
Between the day they become pain-free and Day14, subjects no longer take study 
medication, but continue to record pain levels, narcotic usage, and diet.  Subjects receive a 
second follow up call by a study team member on Day 14 (+/- 1 day) to review compliance 
with medication, and adverse events or complications.  Subjects receive a final call on Day 
30 (+/- 2 days) to review final outcomes (adverse events, complications) and to ensure return 
of the diaries to the study team.  
As noted above, any complications during this period are managed per clinical care, with 
their occurrence and outcomes recorded for study purposes. 
3.2 Allocation to Treatment Groups and Blinding 
Before surgery, subjects are randomized to either celecoxib or placebo.  Randomization 
sequence will be generated and maintained by the CHOP Investigational Pharmacy.  The 
assignment will be concealed from both subjects and investigators.  This blinding will be 
maintained throughout the study.  Breaking the blind will only occur if the information is 
required in an emergency situation.  This is very unlikely, as the clinical management of 
complications such as bleeding does not depend upon on a subject’s current medications.   
Blinding of subjects will be further assured by providing both celecoxib and placebo in 
suspensions of identical appearance and taste.  This should not be difficult, as celecoxib 
does not have a characteristic taste [Krishnaswami et al 2012]. 
Siblings undergoing surgery on the same day will be randomized to the same treatment 
group. 


 
  
 
 
 
13 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The total study duration per subject will be up to 4 months.  This includes the screening day, 
the lag time until surgery occurs (varies, but is typically 0-3 months), the day of surgery, and 
the postoperative 30 days which include treatment and follow up. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted only at CHOP. 
Recruitment will stop when there are 180 subjects with evaluable data.    It is expected that 
approximately 300 subjects will be enrolled to produce 180 evaluable subjects (those who 
return their Study Diary and properly log rescue medication consumption).  
3.4 Study Population 
3.4.1 Inclusion Criteria 
1) Males and females age 3 to 11 years inclusive.   
2) Scheduled to undergo tonsillectomy (with or without adenoidectomy). 
3) Weight ≥ 10 kg. 
4) Girls ≥ 11 years of age must have a negative urine/serum pregnancy test on the day of 
surgery and must use an acceptable method of contraception, including abstinence, a 
barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the 
duration of the study. 
5) Parental/guardian permission (informed consent) and if appropriate, child assent. 
 
The inclusion age range (3-11 years) was chosen due to the demographic of the surgical 
population, and in order to reduce for variability in efficacy measures.  First, the large 
majority of tonsillectomy procedures are performed in the younger age group (for example, 
between September 2013 thru June 2014, 1421 tonsillectomies were performed at CHOP in 
the age 3-11 group vs. 140 for age >=12).  Second, the young patients are historically more 
likely to experience readmission due to pain (e.g., dehydration ) (40 readmissions vs. 9 at 
CHOP during the same period, respectively).  Third, in clinical experience, adolescent 
patients experience substantially higher pain levels, and display much wider variation in 
intensity, narcotic consumption, and outcome measures, such as time out of school or time 
to return to normal diet.  This may be simply due to behavioral variations in teenagers, but 
may also be in part due to their different indications for tonsillectomy (chronic tonsillitis, 
versus mainly sleep disordered breathing in the younger patients).   Thus, inclusion of 
adolescents would add undesirable variability in efficacy measures.  Fourth, bleeding risk is 
higher in teenagers and adults [Wei et al, 2000].  Until the bleeding risk from celecoxib is 
better defined from studies like this, this fact justifies postponing inclusion of this older age 
group until a future study.   


 
  
 
 
 
14 
3.4.2 Exclusion Criteria 
1) Prior tonsillar surgery. 
2) Concomitant surgical procedure that adds more than mild additional pain.  Note: ear 
tubes are always permissible. 
3) Coagulation disorder, or any other hematologic disorder that affects clotting or results in 
anemia. 
4) Moderate to severe asthma, defined as subjects who either (1) have daily symptoms 
requiring daily use of short-acting bronchodilators, or (2) had an exacerbation in the last 
3 months requiring admission, ED visit, or systemic corticosteroid administration.  
5) Any degree of aspirin-sensitive asthma, or any history of asthma exacerbation caused by 
NSAID use. 
6) Severe obstructive sleep apnea that requires use of CPAP or BiPAP. 
7) Significant chronic pulmonary disease, defined as subjects requiring oxygen therapy, 
ventilator support, or positive pressure therapy. 
8) Significant cardiac disease, defined as any one of the following: cardiovascular disease, 
structural cardiac anomalies, prior cardiac surgery, or requirement for cardiac anesthesia.   
9) Severely obese (BMI > 99th percentile for age). 
10) History of hepatic or renal disease, or condition that impairs hepatic or renal function. 
11) Juvenile rheumatoid arthritis (JRA). 
12) History of GI bleeding, or chronic GI condition that would increase risk of bleeding, 
ulceration, or perforation 
13) Hypertension.  
14) Craniofacial syndromes. 
15) Syndrome or neurologic condition that would hinder accurate assessment of 
postoperative pain. 
16) Inability to feed orally or take oral pain medication. 
17) Chronic pain disorders, or otherwise requiring pain medication more than once weekly. 
18) Laboratory abnormalities on the preoperative CBC: 
• Hemoglobin  
< 9 gm/dL 
• Platelet count 
< 100,000/mm3 
19) Any investigational drug use within 30 days prior to enrollment.  
20) Pregnant or lactating females.  
21) Parents/guardians or subjects who, in the opinion of the Investigator, may be non-
compliant with study schedules or procedures. 
22)  Hypersensitivity or allergic reactions to celecoxib, aspirin, or other NSAIDs, including 
asthma flare ups 
23) Allergy to sulfonamides or calcium carbonate. 
 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  


 
  
 
 
 
15 
4 
STUDY PROCEDURES 
Please see also the Table of Procedures.  
4.1 Pre-op Phase 
• Informed Consent / Assent 
• Review Inclusion/Exclusion Criteria  
• Medical Record Review 
• Record data from clinical care: Demographics, Medical History, Physical Exam, 
height, weight, laboratory test (CBC with platelet count), prior/concomitant 
medications 
• Randomization – performed prior to surgery day. 
4.2 Study Treatment Phase (Postop day 0 until pain-free, maximum 10 days)  
This Phase includes the day of surgery (Day 0), and the postoperative days (maximum 10), 
during which subjects receive study medication. 
4.2.1 Day of Surgery (Day 0) 
• Clinical Care:  Surgery and General Anesthesia, Vital Signs, Pregnancy Test, 
Medications, preoperative CBC with platelet count (if not already reviewed), give 
prescription for oxycodone and acetaminophen 
• Dispense study drug, provide instructions 
• Start study medication 
• Dispense Study Diary  
• Medical Record Review 
• This visit including the surgery may be either at the CHOP Perioperative Complex or 
at one of the CHOP Ambulatory Surgery Centers. 
4.2.2 Telephone Call 1 (Day 3 +/- 1) 
• Assess pain control and any problems or questions with medications or diary 
• Assess possible adverse events.  Includes specific query about the occurrence of skin 
rash and review of oral fluid intake and urine output to assess for dehydration. 
• If volume depleted, referral to ED.   


 
  
 
 
 
16 
• If dehydration serious enough to require IV fluids, or elevation of serum creatinine 
as specified above, discontinue study medication. 
• Subjects reminded to call for inadequate fluid intake or urine output. 
• Assess compliance with study drug and diary 
• Medical Record Review 
4.3 Follow-up Phase (Discontinuation of study drug to Postop day 30) 
This Phase begins after the last dose of study medication.  
4.3.1 Telephone Call 2 (Day 14 +/- 1) 
• Assess pain control and any problems or questions with medications or diary 
• Assess possible adverse events  
• Assess compliance with study drug and diary 
• Drug accountability calculation 
• Medical Record Review 
4.3.2 Telephone Call 3 (Day 30 +/- 2) 
• Assess possible adverse events  
• Arrange return of Study Diary. 
4.4 Unscheduled Visits 
Complications are common during the 2-week postoperative recovery after any 
tonsillectomy, with hospital readmission rates currently ranging between 5-10% at our 
institution.    These complications include hemorrhage, refractory pain, refractory 
nausea/vomiting, and dehydration, and will be managed according to usual clinical care 
pathways, which include referral to the ED as appropriate.  There are no changes in these 
pathways related to this study.   However, the occurrence and outcomes of such visits will 
be recorded for study purposes.  
In the event that there are problems related to study procedures that are outside the usual 
pathways for post-tonsillectomy clinical care, subjects will be triaged by our phone nurses, 
and brought into the Otolaryngology Clinic or ED as appropriate, for evaluation by one of 
our attending surgeons.  
4.5 Concomitant Medications 
All prior and concomitant medications used from Days 0-14 will be recorded. The dates of 
administration, dosage, and reason for use will be included.  


 
  
 
 
 
17 
The following concomitant medications are prohibited while receiving study drug: 
• Other NSAIDs including aspirin 
• Antiplatelet agents, anticoagulants (bleeding risk) 
• ACE inhibitors or Angiotensin II receptor blockers 
• Antibiotics (systemic only):  Aminoglycosides, fluconazole, fluoroquinolones 
• CYP2D6 substrates: Aripiprazole, codeine 
• CYP2C8 substrates 
• CYP2C9 inducers or inhibitors 
• Corticosteroids (systemic only) 
• Cyclosporine 
• Digoxin, Lithium, Desmopressin, Mifepristone, Nitric Oxide agents 
• Certain antihypertensives – Beta blockers, eplerenone, hydralazine 
• Chemotherapy agents: Doxorubicin 
• Hormones:  estrogen derivatives (thrombogenic enhancement) 
• Loop or thiazide diuretics, tramadol, SSRIs, tamoxifen, prostaglandins, tenofovir 
 
4.6 Rescue Medication Administration 
All subjects are prescribed oxycodone and acetaminophen as clinical care.  There is no 
difference in dosing compared to their use outside the research.  However, there is a slight 
modification to the usual clinical instructions as follows.  In current clinical care, patients 
are instructed by the PACU nurses to use the acetaminophen and oxycodone around the 
clock for the first few days, until their pain becomes less intense.  The number of days are 
not specified.  Patients then switch to using both as-needed.  In this study, all subjects will 
take their acetaminophen around the clock for 5 days, with oxycodone reserved for 
breakthrough pain (but still up to every 4 hours as needed).  After 5 days, both rescue 
medications are taken as needed. 
Up-dosing of oxycodone is common, especially within the first week, and we expect this 
will be true for study subjects as well.  These are usually managed by the phone triage nurse 
practitioners, who are permitted to increase oxycodone dose up to 0.1 mg/kg/dose every 4 
hours if necessary, with referral to the ED if pain is still not controlled. Throughout the 
study, subjects will record the quantity they consume, as this is a key outcome variable.  We 
expect that subjects receiving placebo will consume similar quantities as children outside the 
research, and that subjects on celecoxib will consume a lower quantity. 
4.7 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued at the discretion of the Investigator for lack of adherence to study 
treatment or visit schedules, AEs, or if it is felt by the Investigator that continuing the study 
would in any way endanger their health.  Any subject who withdraws will continue to have 
appropriate pain control, since they were already prescribed standard of care analgesics. 
Postoperative hemorrhage is not rare after tonsillectomy (typical rates 2-5%), and so is 
expected to occur to some subjects in this study.  Subjects who experience postoperative 


 
  
 
 
 
18 
hemorrhage will be instructed to immediately discontinue the use of study medication, in 
addition to the usual instructions for management of this complication.  However, these 
subjects will not be withdrawn from the study, but rather will continue in the follow-up 
phase of the study.  This includes recording pain diaries and receiving follow up calls per the 
schedule described.  This will allow assessment of final outcomes for these subjects, and 
maintain the blinding needed for scientific validity of the study. 
Subjects who develop a rash while taking study medication will be instructed to immediately 
discontinue the study drug, but to continue to use their rescue medication as per clinical 
care.  As was the case for hemorrhage, these subjects will not be withdrawn from the study, 
but rather will continue in the follow-up phase of the study.  This includes recording pain 
diaries and receiving follow up calls per the schedule described.  This will allow assessment 
of final outcomes for these subjects, and maintain the blinding needed for scientific validity.  
As described previously (section 3.1.2), subjects who develop significant dehydration will 
be assessed in the ED.  Those who require IV fluids, or have abnormalities in laboratory 
assessment (creatinine), immediately discontinue the study drug, but continue to use their 
rescue medication as per clinical care.  As was the case for hemorrhage, these subjects will 
not be withdrawn from the study, but rather will continue in the follow-up phase of the 
study.  This includes recording pain diaries and receiving follow up calls per the schedule 
described.  The study team will also follow up with the subject’s PCP to ensure resolution of 
any abnormalities of lab values or renal function.  
The Investigator may also withdraw subjects who violate the study plan, or to protect the 
subject for reasons of safety or for administrative reasons.  It will be documented whether or 
not each subject completes the clinical study. If the Investigator becomes aware of any 
serious, related adverse events after the subject completes or withdraws from the study, they 
will be recorded in the source documents and on the CRF. 
4.7.1 Early Termination Study Visit 
Subjects who withdraw from the study will have an exit phone call follow up that includes 
all elements outlined in Call 2 and Call 3 in the Visit Table. 
STUDY EVALUATIONS AND MEASUREMENTS 
4.8 Screening and Monitoring Evaluations and Measurements 
4.8.1 Medical Record Review 
The following will be recorded from the medical record, which includes surgical office visit 
notes completed just prior to screening, operative notes from the tonsillectomy procedure, 
and perioperative nursing and anesthesia notes: Date of birth, date of surgery, operating 
surgeon.  Height, weight. Other comorbid medical conditions.  Prior/concomitant 
medications. Prior surgical procedures.  Diagnosis necessitating surgery (e.g. sleep-
disordered breathing, chronic tonsillitis).  Data from preoperative polysomnogram, if 
performed.  Tonsil size from operative note.  Surgical details (method of tonsil removal, 
cautery wattage/mode, complications, procedure time).  Analgesics given during procedure 
and in PACU, including doses.  Corticosteroids and their doses given intraoperatively. 


 
  
 
 
 
19 
4.8.2 Laboratory Evaluations 
Values are recorded from certain laboratory studies done routinely for clinical care.  These 
are listed below.  There are no research-only laboratory studies.  
4.8.2.1 Hematology Tests 
As part of clinical care, all patients without a recent hemoglobin and platelet count (within 
the prior 6 months) undergo a preoperative blood draw (CBC with platelet count).  Results 
are recorded for this study.  If any preoperative coagulation studies are performed for 
clinical care, these data are also recorded.      
4.8.2.2 Pregnancy Testing 
As part of clinical care prior to administering general anesthesia, a urine pregnancy test is 
always performed for female subjects ≥ 11 years of age and girls <11 years who are 
physically capable of becoming pregnant.  Results are recorded for this study. If the test is 
positive, subjects will be withdrawn from the study. 
4.9 Efficacy Evaluations 
4.9.1 Days receiving narcotic medication 
Following Sobol et al [2006], the day a subject is considered “off” narcotic medication is 
defined as the day they received either 0 or only 1 dose of narcotic.  This number is recorded 
from the number of doses of oxycodone subjects record each day in their Study Diary.  
4.9.2 Pain Scales (See Appendix) 
The subject’s pain level is recorded on the study Diary in the recovery room, then twice 
daily, just before receiving each dose of study medication.  The 10-point Wong-Baker 
FACES pain scale is used for all ages (scale is validated for ages 3 and above) [Wong and 
Baker 1988].  Alternatively, children 10 and older may mark their pain on the customary 10-
point pain scale shown. 
4.9.3 Measurement of Oxycodone and Acetaminophen Usage  
Oxycodone and acetaminophen dosages are prescribed by the surgeon after the procedure, 
and are most commonly oxycodone suspension 0.075 mg/kg/dose every 4 hours as needed, 
and acetaminophen syrup 15 mg/kg/dose every 4 hours as needed.  There will be no change 
in these prescribed doses, except that subjects will take the acetaminophen around the clock 
for the first 5 days.  Quantity administered in the PACU is recorded from flowsheets.  Initial 
volume received from the pharmacy, and drug concentration, are recorded.   Volumes of 
each dose given at home (in increments of 0.1 mL) are recorded by caregivers on the Study 
Diary.   
At the end of the two week postoperative period, during Telephone Call #2, caregivers will 
measure the remaining volume of unused oxycodone and acetaminophen, to the nearest 1 
mL, using an appropriate syringe (e.g. 20 cc) given to them on the surgery day.   


 
  
 
 
 
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4.9.4 Return to Normal Diet Assessment 
Each day on the study diary, subjects record whether their diet was predominantly liquid 
diet, soft diet, or normal diet that day. 
4.9.5 Data Collection from Hospital Readmissions  
Readmission rates for excess postoperative pain and dehydration are considered efficacy 
measures because they are caused by inadequate pain control. Medical records are reviewed 
from each hospital visit (Emergency Department, Emergency Dept. Extended Care Unit, or 
inpatient records): date, reason for readmission, diagnosis, laboratory studies, medications 
administered (analgesics, antiemetics, steroids, antibiotics), and other treatment 
administered (intravenous fluids, oral fluids, surgical reoperation, observation for bleeding). 
4.10 Safety Evaluation 
Subject safety will be monitored by adverse events, which include the serious adverse event 
of postoperative hemorrhage.  The PI reviews SAEs immediately, and other AEs every 2 
weeks with the study team.  As described in section 5.2.4 above, data is collected for all 
hospital readmissions in the 30 days following surgery, and this includes the AE data listed 
in that section.   Further details are in Section 8 below. 
 


 
  
 
 
 
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5 
STATISTICAL CONSIDERATIONS 
5.1 Primary Endpoint 
The primary endpoints are (1) number of days on narcotic medication, and (2) total amount 
of rescue narcotic pain medication consumed.   
5.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• Efficacy based on time to return to normal diet, quantity of rescue acetaminophen used, 
and rate of readmission for dehydration or excessive pain.   
• Safety based on rates of postoperative hemorrhage. 
• Safety and tolerability of celecoxib based on Adverse Events.  
 
5.3 Statistical Methods 
5.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
5.3.2 Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all 
subjects who are randomized.   
The primary efficacy endpoint will be (1) the difference in number of days on narcotic 
medication, and (2) the difference in total amount of rescue narcotic pain medication 
consumed in the 2-week postop period.  For the latter, total amount of oxycodone consumed 
will be expressed as morphine equivalents per kg body weight. 
Secondary efficacy endpoints will include the difference in time to return to normal diet, 
difference in amount of rescue acetaminophen used, and difference in rate of readmission 
for dehydration or excessive pain.   
The above efficacy variables will be compared between the two treatment groups by a two-
sample t-test. 
Note:  Statistical analysis is the same for all subjects, regardless of whether or not they 
became pain-free and discontinued study drug before the maximum10 days of dosing. 
Subjects who miss more than 3 of the scheduled doses of study drug during the first 5 days, 
will not be included in the efficacy analysis.  These subjects continue their study medication 
per protocol, but their efficacy data will be analyzed separately at the end of the study.  All 
will continue to be included in the safety analysis.  


 
  
 
 
 
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5.3.3 Safety Analysis 
All subjects entered into the study at the preoperative visit will be included in the safety 
analysis. The frequencies of AEs by type, body system, severity and relationship to study 
drug will be summarized. SAEs (if any) will be described in detail.  The frequency of 
postoperative hemorrhage will be summarized. 
Postoperative hemorrhage and AE incidence will be summarized along with the 
corresponding exact binomial 95% two-sided confidence intervals. 
5.4 Sample Size and Power 
Sample size estimation was based on available data from a prior pilot study of celecoxib use 
at University of Iowa in adults after tonsillectomy, and baseline data from a tonsillectomy 
pain study done at CHOP (referred to below as the Microdebrider study) [Sobol et al 2006].  
Sample size estimates were made separately for both primary efficacy endpoints, based on 
the available data.  This was done with two-sample power analysis based on average values, 
using an alpha of 0.05 and beta 80%.  If variance for the experimental group was not 
available, an assumption of equal variance as the control group was made. 
We determined the sample size needed to detect the following meaningful differences:  a 
reduction of 1 day in number of days on narcotic medication, as recommended in Sobol et al 
[2006], and a reduction of 20% in total narcotic consumed.  
Days on narcotic pain medication:  The CHOP Microdebrider study reported that children in 
their control group required narcotic medication a mean 8.2 days (SD 2.7 days).  These 
children underwent standard electrocautery tonsillectomy, and so were essentially identical 
to our placebo control group.  Based on these results and assuming equal variance in both 
groups, a sample size of 90 per group is required to detect a 1-day improvement in this 
outcome variable. 
Total narcotic pain medication consumed:  The University of Iowa pilot study [Van Daele et 
al 2014] reported rescue narcotic consumption in a small group of adults randomized to 
either celecoxib or placebo.  Narcotic equivalents were consumed as follows: 632 (381) in 
placebo group; 262 (148) in celecoxib group.  Based on these results, a sample size of 65 per 
group is required to detect a 20% improvement in this outcome variable. 
We expect a dropout rate of up to 40%, mainly from subjects who never return their Study 
Diary, or who do so without accurately recording total narcotic consumed.  This estimate is 
based on our experience with diary returns in prior tonsillectomy studies, which are lower 
than other trials because of the fact there is no routine post-operative clinic visit after routine 
tonsillectomy surgery.  Based on this rate, a final sample size estimate of 150 per group is 
needed to yield the 90 per group needed to assess our primary endpoints. 
5.5 Interim Safety Analysis 
No interim analysis for efficacy will be performed in this study.  However, an interim 
analysis for safety may be performed under certain conditions described below. 


 
  
 
 
 
23 
As noted previously, postoperative hemorrhage is not rare after tonsillectomy (typical rates 
2-5%), and so is expected to occur in 6 to 14 children over the entire study.  We anticipate 
similar hemorrhage rates between the two groups, so up to 7 children per group. As noted 
earlier, these subjects discontinue study drug and undergo clinical care, but remain blinded 
and continue on the study to undergo monitoring procedures.   
Even though blinded, the PI can monitor the hemorrhage rates in each group separately 
throughout the study.  An interim safety analysis (with unblinding) will then be performed in 
either of the following cases: 
• If, after the first 50 subjects are treated in either group, greater than 5 children 
experienced significant hemorrhage in that group, OR 
• If at any point in the study, the PI otherwise judges that there is a concerning 
difference in bleeding rate between the 2 groups. 
The study would then be stopped if the unblinding then revealed both that the higher rate 
occurred in the celecoxib group, and that the hemorrhage events were probably or definitely 
related to the study drug.    
 
 


 
  
 
 
 
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6 
STUDY MEDICATION   
6.1 Description 
The study drug is celecoxib (Celebrex, Pfizer, or generic equivalent).  Celecoxib is a 
nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and 
antipyretic activities. The mechanism of action is believed to be due to inhibition of 
prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at 
therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase-1 
(COX-1) isoenzyme.  
Suspension formulations:  While a suspension of celecoxib is still not commercially 
available, several investigational suspensions have been studied.  The FDA reviewed Pfizer 
RR-754-00049 reporting pharmacokinetic study of celecoxib suspension (Study 195), which 
included suspensions of 50 mg/5mL and 100 mg/5 mL in 242 children at 60 sites.  Of these, 
202 went on to open-label use of the suspensions at 3 mg/kg BID.  [FDA,  BCPA Summary 
for NDA 20-998, Supplement 021].   In a published study, PK and efficacy were studied in 
children with JRA using an investigational suspension, in 152 JRA patients aged 2 to 17 
years [Krishnaswami et al 2012].  The Children’s Hospital of Eastern Ontario reported on 
their 10 mg/mL suspension in Ora-Blend [Donnelly et al, 2009].   This suspension is stable 
for at least 90 days, either at room temperature or refrigerated.  This suspension was used 
safely in their recent large clinical trial in pediatric tonsillectomy [Murto et al 2015]. 
For this study, bulk drug will be obtained by the CHOP or Penn Investigational Pharmacy 
and mixed into suspension at concentration 100 mg/5 mL (20 mg/mL) in Ora-Blend or 
equivalent, following Donnelly et al [2009].   
Placebo, with appearance, taste and consistency as similar as possible to the active drug, will 
be mixed in identical fashion.   Placebo consists of calcium carbonate powder suspended in 
the same syrup as the active drug.  The dose of elemental calcium is 3 mg/kg/day.  Calcium 
carbonate in this concentration provides a cloudy appearance identical to celecoxib 
suspension, with no characteristic taste.  
6.1.1 Packaging 
Celecoxib and placebo capsules or bulk powder are obtained from the manufacturer by the 
CHOP Investigational Pharmacy.  They are then suspended as above and stored in amber 
bottles under refrigeration until they are dispensed to the subject, after which they will be 
kept at room temperature.  They are labeled in a fashion that maintains double blinding.  
Total volume dispensed to each subject is enough to supply a total 20 doses. 
6.1.2 Labeling 
Labeled by the Investigational Pharmacy as described above. 
6.1.3 Dosing 
Dosing of celecoxib is 6 mg/kg BID, maximum 300 mg BID.  All ages are given the 
suspension, following standard practice after tonsillectomy.  The first dose is given 


 
  
 
 
 
25 
preoperatively, within 1 hour prior to entering the operating room.  The second dose is given 
at bedtime on the night of surgery.  Subsequent doses are given 12 hours apart. 
6.1.4 Treatment Compliance and Adherence 
Caregivers are instructed in study drug administration by study staff during their stay in the 
recovery room.  Compliance with drug administration is assessed at each Postoperative 
telephone call, and also upon review of the Study Diary returned at the end of the study.  
6.1.5 Drug Accountability 
At the Day 14 telephone call, the study team member will ask the patient to measure the 
amount of study drug remaining.  Since all subjects initially received 20 doses, calculation 
of accountability is straightforward.  This information is entered into the CRF and 
communicated to the Pharmacy.  The family will then dispose of the unused medication at 
home.   
Adequate records of study drug receipt and disposition will be maintained by the CHOP 
Pharmacy.  Records of receipts, investigational drug orders, dispensing records, and 
disposition forms will be examined during the course of the study.  The purpose of these 
records is to ensure regulatory authorities that the investigational drug will not be distributed 
to any person who is not a study subject under the terms and conditions set forth in this 
protocol.  The study medication is to be prescribed by the Investigator or designee and may 
not be used for any purpose other than that described in this protocol. 


 
  
 
 
 
26 
7 
SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  The procedures for 
obtaining this information (via phone interview, recording of data from unscheduled 
admissions, and study diaries) were described in Section 5.1, with the schedule in Table 1. 
7.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  
7.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received the 
study drug (celecoxib or placebo).  The occurrence does not necessarily have to have a 
causal relationship with the treatment.  An AE can therefore be any unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
7.4 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• death, 
• a life-threatening event (at risk of death at the time of the event),  
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• a persistent or significant disability/incapacity, or 
• a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 


 
  
 
 
 
27 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
7.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study drug should be characterized using one of the 
following terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, 
unlikely or unrelated.  
7.5 Anticipated SAEs 
The following are the known SAEs related to surgery that are anticipated based on current 
clinical experience, and the approximate rates that are expected.  These SAEs will be 
recorded and their rates monitored carefully, but are reported differently to the IRB from the 
unanticipated SAEs, as discussed in Section 8.6 below. 
1. Postoperative hemorrhage (expected rate up to 10%) 
Hemorrhage is not rare after tonsillectomy, and so is anticipated in both treatment 
groups.  Rates are typically 2-5%, but rates up to10% have been observed in some 
months at CHOP.  Hemorrhage is always considered a life-threatening SAE.  We 
further anticipate that rates of the two groups will be similar.  Hemorrhage events, 
including hospitalization and surgical management, will be recorded, and their rates 
and outcomes monitored by the PI throughout the study. 
2. Postoperative readmission (expected rate up to 10%). 
From internal quality monitoring data over the last 2 years, rates of readmission of 
up to 10% have been observed.  Historically these result from hemorrhage (described 
separately above), pain-related complications (uncontrolled pain, dehydration), and 
side effects from narcotics or anesthesia (e.g., nausea, vomiting). 
3. Prolonged initial admission (expected rate up to 30% of those kept overnight).   
Children who are admitted overnight after surgery often stay hospitalized a second 
night or longer.  The most common reason is inadequate oral intake, which is most 
common in the younger children.  Other reasons include inadequate pain control, the 
need for more time to wean off supplemental oxygen, or the need for an additional 
night of respiratory monitoring due to episodes of oxygen desaturation recorded the 
first night. 
 
 


 
  
 
 
 
28 
7.6 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all unanticipated, serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be 
filed using the eIRB system and in accordance with the timeline below.   
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Death or Life Threatening 
SAEs (not listed in Section 
8.5)*  
24 hours 
Within 2 calendar days 
All other SAEs  
(not listed in Section 8.5)* 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
 
*For the Anticipated SAEs listed in Section 8.5 above, the Investigator will report these 
events differently than other SAEs.  If rates of Anticipated SAEs fall within the expected 
ranges listed in Section 8.5, they will be reported similarly to AEs, as a summary at the time 
of Continuing Review.  However, if their rates exceed the expected ranges, they will be 
reported promptly to the IRB as per the above table (i.e., 24 hours for life threatening SAEs, 
7 days for all other SAEs).  Death will always be reported within 24 hours regardless of the 
circumstances. 
7.6.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
7.7 Investigator Reporting of Serious Adverse Events to Funder 
Reporting of SAEs will be consistent with funder requirements (Safety Reporting Reference 
Manual for IIR Studies with Pfizer Products).  Subjects are identified only by Study ID 
number.  
7.8 Medical Emergencies 
On the day of surgery, initial study procedures occur within the perioperative complex at 
CHOP or a CHOP ambulatory surgery center.  Any medical or surgical emergencies at that 


 
  
 
 
 
29 
time are handled in the usual fashion by the anesthesia and surgical specialists at the site.  
Postoperatively, some patients are discharged (Day Surgery) while others are admitted 
overnight for observation, as per clinical care.  For the latter, any emergencies during the 
admission are handled by the Otolaryngology inpatient service.  During the home recovery 
period for all subjects, medical emergencies common during the postoperative period (for 
example, dehydration and hemorrhage) are managed in the same way as outside the 
research, per well-established protocols.   Any unusual emergencies besides those 
occurrences are not expected, but if they occur, each will be assessed by our postoperative 
triage phone nurses, or the physician on call after hours, with subjects directed to the 
Emergency Department as needed. 


 
  
 
 
 
30 
8 
STUDY ADMINISTRATION 
8.1 Treatment Assignment Methods 
8.1.1 Randomization 
Between the Pre-op Visit and Surgery Day, subjects are randomized in equal numbers to 
each treatment group.  Randomization sequence will be generated and maintained by the 
CHOP Investigational Pharmacy.  The resulting group assignments and Study ID numbers 
are used to prepare study medication and containers for use on Surgery Day.  Siblings 
undergoing surgery on the same day will be randomized to the same treatment group. 
8.1.2 Blinding 
Treatment group assignment will be concealed from subjects, investigators, and caregivers, 
including perioperative personnel and phone triage nurses.  This blinding will be maintained 
throughout the study.   
Blinding of subjects will be further assured by providing both celecoxib and placebo as 
identical-appearing suspensions and packaging. Because drug is administered as a 
suspension, blinding will be further assured by the ensuring placebo tastes as similarly as 
possible to celecoxib. 
8.1.3 Unblinding 
Breaking the blind will only occur if the information is required in an emergency situation.  
This is very unlikely, as the clinical management of complications such as bleeding does not 
depend upon on a subject’s current medications.   The most notable example of such a 
situation is hemorrhage.   All patients who experience hemorrhage immediately stop their 
study drug, whether active or placebo, and then subsequent clinical management is the same 
regardless of which group they were assigned.  
8.2 Data Collection and Management 
Source documents consist of hospital and otolaryngology records and will be viewed only 
long enough to collect data specified.  Data is logged into REDCap kept on encrypted 
hospital-issued computers.  Data will be managed and stored using the research-focused 
electronic data capture system REDCap, under an agreement with the software’s 
development consortium, led by Vanderbilt University. REDCap supports two secure, web-
based applications designed exclusively to support data capture for research studies.  
REDCap as implemented at CHOP includes daily destructive database backup files that are 
stored on the database server and are deleted only after successful backup of the entire 
database to file.  Data and backups are stored in the CHOP Research Information Systems 
Storage Area Network (SAN).  Access to the SAN directories where data are stored will be 
limited to Research Information Systems personnel, with authentication performed using 
CHOP’s enterprise Active Directory service. 
Data are recorded either directly into REDCap, or initially on paper forms then transferred to 
REDCap in a timely fashion, then the paper forms destroyed.  The datasheets and REDCap 
database will contain only coded information.  Only limited datasets will be exported from 


 
  
 
 
 
31 
REDCap.  All PHI will be contained in REDCap.  Access to the data in REDCap will be 
limited only to study team members. 
All Study Team members have completed HIPAA and all required institutional training 
relevant to clinical research. 
1. 
Confidentiality of Data.  The investigators will not take data off-site.  Data 
will be coded in REDCap by study number.    
2. 
Security.  Data are secured by REDCap under the protections described 
above. 
3. 
Deidentification or destruction.  Identifiers will be destroyed 5 years after 
results are accepted for publication. This is necessary in case of drug-related questions 
from the FDA or other regulatory agencies.  During the 5-year period, identifiers are 
kept exclusively in REDCap. Thus, the coding is maintained. 
4. 
Only study team members will have access to all the identifiable information. 
8.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy. The Investigators and other personnel 
will not use such data and records for any purpose other than conducting the study, unless 
the IRB approves (or exempts) other uses. Safeguards are described under Data Collection 
and Management.  If any investigator leaves the institution he or she will surrender any 
identifiable data.  It is expected that publications or presentations will include only 
aggregate data.   
Confidentiality will be maintained by REDCap, which assigns each subject with a Subject 
ID and keeps identifying information separate from the data.   Once data is collected, the 
PHI will be accessed only in the event, prior to publication, that the charts need to be 
accessed a second time.  This would occur if only if questions arise from reviewers or 
regulatory agencies that were not recorded during the original data collection.   Thus, 
maximum privacy of patient identifying information is ensured, while at the same time 
maintaining a secure link necessitated by the nature of this study. 
During the data collection process, the temporary paper data collection forms, charts and 
other records will not leave the CHOP premises, and will be kept in a locked office.  Access 
will be limited only to the study team members.   Digital data will be accessed only using 
CHOP hospital computers and secure servers.  
8.4 Regulatory and Ethical Considerations 
8.4.1 Data and Safety Monitoring Plan 
The P.I. will be responsible for monitoring the integrity of the data and the safety of all 
subjects.   The PI reviews SAEs immediately, and other AEs during regular meetings with 
the study team approximately every 2 weeks.  As described in section 5.2.4 above, data is 
collected for all hospital readmissions in the 30 days following surgery, and this includes the 


 
  
 
 
 
32 
AE data listed in that section.   AEs are reported to the IRB as noted in the above sections.  
There is no Data Safety Monitoring Board for this study. 
8.4.2 Risk Assessment 
Risk level in subjects receiving celecoxib is greater than minimal, and is detailed below.  
Risk level in the placebo group is minimal and is discussed further at the end of this section. 
1. Risks of Celecoxib Administration. 
Celecoxib has a favorable safety profile in children and adults, with most of its adverse 
effects being associated with chronic, long term use, or with use in certain conditions not 
applicable to children or to the current study (e.g., cardiovascular thrombotic disease).  
Importantly, essentially all of the risks described below are not unique to celecoxib, but 
rather apply to all NSAIDs.  Of course, other NSAIDs are already used extensively in 
children of all ages, especially for short term therapy, including postoperative pain control. 
Below, we first discuss risks most applicable to short-term administration in this study, 
followed by discussion of adverse effects seen during long-term treatment.  Each is followed 
by discussion of risk minimization in the current study.  The risk discussions are based on 
information from the manufacturer (Pfizer Celebrex Full Prescribing Information 
document).  
Risks applicable to short-term therapy 
Aspirin-Sensitive Asthma -- All NSAIDs may precipitate bronchospasm in patients with 
Aspirin triad asthma.  It is well known that aspirin may cause severe bronchospasm in 
patients with aspirin-sensitive asthma, which can be fatal. Since cross reactivity between 
aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celecoxib 
could cause this event in patients with this form of aspirin sensitivity.  More generally, the 
manufacturer recommends using celecoxib with caution in patients with preexisting asthma.   
This risk is minimized in the present study by excluding subjects with aspirin-sensitive 
asthma, any prior severe reactions to aspirin or NSAIDs, or any form of moderate to severe 
asthma, even in the absence of known aspirin sensitivity. 
Anaphylactic Reactions -- As with all NSAIDs in general, rare anaphylactoid reactions have 
occurred in patients, even without known prior exposures. In post-marketing experience 
reported by the manufacturer, rare cases of anaphylactic reactions and angioedema have 
been reported in patients receiving celecoxib. This risk is minimized in the present study by 
excluding subjects with any prior reactions to aspirin or NSAIDs. 
Skin Reactions -- Celecoxib is a sulfonamide and can cause rare but serious skin reactions 
such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, 
which can be fatal.  These serious events can occur without warning and in patients without 
prior known sulfa allergy.  This risk is minimized in the present study by excluding subjects 
with sulfonamide allergy, and subjects are informed about the signs and symptoms of 
serious skin manifestations and counseled to stop the study drug at the first appearance of 
skin rash or any other sign of hypersensitivity. 


 
  
 
 
 
33 
Postoperative Hemorrhage -- As described in earlier sections, use of celecoxib does not 
appear to increase bleeding risk after surgical procedures.  On the contrary, Cox-2 inhibitors 
actually reduce the amount of blood loss during orthopedic procedures [Li et al 2009].  
Preliminary data after tonsillectomy (discussed above) suggests that bleeding risk is not 
increased for this surgery either.  Nevertheless, since no large studies have yet been 
performed, the effects of celecoxib on bleeding risk after tonsillectomy must be considered 
unknown at this time.  Of course, our hypothesis is that celecoxib will actually reduce 
bleeding risk, due to its absence of platelet inhibition. This risk is minimized in the present 
study by (1) the nature of celecoxib as a selective COX-2 inhibitor; (2) excluding subjects 
with coagulation disorders, and (3) by close monitoring of the rates of this SAE as described 
in this protocol. 
Other side effects reported in clinical trials: 
Adults – the following side effects occurred at a rate greater than placebo, and in >2% of 
adults, in the pre-marketing controlled arthritis trials.  Notably, all of these were the same or 
less than for the other NSAIDs in the trial (naproxen, diclofenac, ibuprofen): 
Gastrointestinal 
Abdominal Pain 
Diarrhea 
Dyspepsia 
Flatulence 
Body as a whole 
Peripheral Edema 
Respiratory  
Pharyngitis  
Rhinitis /Sinusitis 
 
Children -- Below (Table 3) are the AEs reported during chronic long term use in children 
for JRA, as reported by the manufacturer.  The side effect profile appears very similar to 
naproxen, another NSAID. 
 
Table 3. Adverse events occurring in >5% of JRA patients in any 
treatment group, by system organ class (% of patients with events) 
 
System Organ 
Class 
Preferred Term 
Celecoxib 3 
mg/kg BID 
 N=77 
Celecoxib 6 
mg/kg BID 
 N=82 
Naproxen 7.5 
mg/kg BID 
 N=83 
Any Event 
64 
70 
72 
Eye Disorders 
5 
5 
5 
Gastrointestinal 
26 
24 
36 
Abdominal pain NOS 
4 
7 
7 
Abdominal pain upper 
8 
6 
10 
Vomiting NOS 
3 
6 
11 
Diarrhea NOS 
5 
4 
8 
Nausea 
7 
4 
11 
General 
13 
11 
18 
Pyrexia 
8 
9 
11 
Infections 
25 
20 
27 
Nasopharyngitis 
5 
6 
5 
Injury and Poisoning 
4 
6 
5 
Investigations* 
3 
11 
7 


 
  
 
 
 
34 
Musculoskeletal 
8 
10 
17 
Arthralgia 
3 
7 
4 
Nervous System 
17 
11 
21 
Headache NOS 
13 
10 
16 
Dizziness (excl vertigo) 
1 
1 
7 
Respiratory 
8 
15 
15 
Cough 
7 
7 
8 
Skin & Subcutaneous 
10 
7 
18 
*Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin 
time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture 
positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, 
Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests 
NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis 
abnormal NOS. 
Risks unlikely in short term use in pediatric subjects: 
Cardiovascular effects --NSAIDs now carry a Boxed Warning regarding this risk.   All 
NSAIDs are associated with increased risk of serious adverse cardiovascular thrombotic 
events, including myocardial infarction and stroke. These risks are increased with long term 
use and pre-existing cardiovascular disease or risk factors.  Celecoxib is believed to be 
similar to all the other NSAIDs regarding this risk.  Likewise, all NSAIDs, including 
celecoxib, also can lead to the onset of new hypertension or worsening of preexisting 
hypertension, and may cause fluid retention or edema in the setting of congestive heart 
failure.  None of these events or effects have been reported in children. 
These risks are essentially nonexistent in our subjects, who are children, and who are 
receiving very short term therapy.  Risk is further minimized by excluding any patient with 
preexisting cardiac disease or hypertension. 
Serious GI events – All NSAIDs, including celecoxib, can cause serious gastrointestinal 
events including bleeding, ulceration, and perforation of the stomach, small intestine or large 
intestine, which can be fatal.  NSAIDs now carry a Boxed Warning regarding this risk.   
These events were reported during chronic use in adults, where the overall rate of 
complicated and symptomatic ulcer rates was reported as 0.78% (CLASS trial).  Higher 
rates were found in adults with risk factors, including prior history of peptic ulcer disease 
and/or gastrointestinal bleeding (10-fold increased risk), concomitant use of oral 
corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of 
alcohol, older age, and poor general health status.  
These risks are exceedingly small in our subjects, who are children and receiving very short 
term therapy.  Risk is further minimized by excluding any patient with history of GI 
bleeding, or chronic GI condition that would increase risk of bleeding, ulceration, or 
perforation, and presence of other risk factors for GI bleeding (aspirin, other anticoagulants, 
chronic steroids).   
Effects on Renal Function – all NSAIDs may compromise renal function, and should be 
avoided in patients with impaired renal function.  Clinical trials show celecoxib is no 
different from the other NSAIDs. This risk is minimized in the present study by excluding 
any subjects with a history of renal disease. 


 
  
 
 
 
35 
Volume depletion may increase the chance of renal injury from NSAIDs [Misurac 2013].  
However, some authors have not found such an association with short term NSAID use 
[Lesko, 1997].  Subjects undergoing tonsillectomy may experience dehydration due to 
inadequate pain control, with rates of readmission for dehydration observed from 1-5% at 
CHOP.  This risk is minimized in the present study as follows: 
1. Excluding any subjects with pre-existing renal disease. 
2. Subjects’ self-monitoring of intake and urine output to ensure early detection of 
dehydration, as described in section 3.1.2. 
3. Nurse call on Day 3 with specific query about dehydration parameters. 
4. Referral of possibly dehydrated subjects to the ED, where electrolytes and renal 
function are assessed, and subjects rehydrated as per standard pathways. 
5. Discontinuation of study drug if dehydration is serious enough to require intravenous 
fluids, or if abnormal renal function is observed (elevated creatinine). 
6. Better pain control in the NSAID group -- we expect subjects in the celecoxib group 
will have better pain control, and thus less risk of dehydration, than placebo subjects 
or children outside the research. 
Effects on Hepatic function --  Borderline elevations of one or more liver-associated 
enzymes may occur in up to 15% of patients taking NSAIDs, and “notable” elevations of 
ALT or AST (approximately 3 or more times the upper limit of normal) have been reported 
in approximately 1% of patients in clinical trials with NSAIDs.  For celecoxib specifically, 
the incidence was lower, in fact similar to placebo (borderline elevation of 6% for celecoxib 
and 5% for placebo, and “notable” elevations in only 0.2% taking celecoxib and 0.3% taking 
placebo).  These risks are exceedingly small in our subjects, who are children on very short 
term therapy.  Risk is further minimized by excluding any patient with a history of hepatic 
disease. 
Coagulation effects in Systemic Onset JIA/JRA:  The preclinical JRA studies found that 
children with systemic onset JRA (without active systemic features) were at risk for the 
development of abnormal coagulation laboratory tests.  This risk is minimized in the present 
study by excluding any subjects with this disease.  
Anemia -- Anemia was observed in chronic celecoxib trials at a slightly higher rate than 
placebo (0.6% vs 0.4%).  This risk is minimized in the present study by excluding subjects 
with preoperative anemia (Hgb <9 g/dL). 
Minimizing Risks of Celecoxib in this Study 
Risks of study medication are minimized as noted above under each risk category.  They are 
also minimized by the study design and execution: 
• Dosing has been used safely in both children and adults.  Further, the same dosing 
was used safely in children for up to 24 weeks [Foeldvari 2009], whereas in the 
present study dosing is only short term (10 days). 
• The exclusion criteria minimize risk by excluding subjects at higher risk of adverse 
effects of celecoxib, as noted above. 
• Adverse events are closely monitored by the PI and study team as described. 


 
  
 
 
 
36 
 
2. Risk Assessment: Placebo administration  
The risk level in the placebo group is minimal, since these subjects essentially undergo the 
same management as would occur outside the research.  Pain levels will be the same as 
current standard of care, as is bleeding risk.  Pain is mitigated by the availability of rescue 
analgesics, which is the same as outside the research.  All subjects receive the same dose 
and quantity of oxycodone/acetaminophen as those currently given to children in clinical 
care.  As in clinical care, placebo subjects receive around-the-clock dosing of 
acetaminophen, but instead of doing so for an unspecified duration, it will be specified as the 
first 5 days.  This should not increase risk to subjects in the placebo group compared to 
standard care.  In fact, it may even reduce risk, as it may result in less total narcotic 
consumption over the first 5 days.   
The placebo excipient (calcium carbonate) is a ubiquitous dietary calcium supplement and 
mild antacid (e.g., Tums).  The dose used in this study (elemental calcium dose of 3 
mg/kg/day) is far lower than therapeutic dosing required for any indication (range 50-150 
mg/kg/day).  Allergy to calcium carbonate is rare, and children with such an allergy are 
excluded at the time of screening.  
3. Risks of other study procedures 
Risks associated with interviews and Study Diary are minimal.  There is risk of temporary 
embarrassment on answering medical questions during interviews. 
8.4.3 Potential Benefits of Trial Participation 
Subjects in the celecoxib group will likely directly benefit from improved pain control, and 
less requirement for narcotic analgesics.  This is meaningful, given the well-known side 
effects of narcotics.  Narcotics are notable for their tendency to cause GI disturbance, 
constipation, of narcotics, including GI symptoms, somnolence and respiratory depression.  
The latter is especially concerning in patients undergoing tonsillectomy for sleep disordered 
breathing, which is the majority of the children in this age group.  In fact, this has been one 
of the main factors motivating the search for alternatives to opioids after this surgery.   
Subjects in the placebo group will not directly benefit from this study. 
This study will have indirect benefits to all children undergoing tonsillectomy, or any other 
surgery, since it may help establish a new alternative to narcotics for postoperative pain.  It 
will also help provide future patients an alternative to traditional NSAIDs that provides 
symptom relief without increasing bleeding risk.  
8.4.4 Risk-Benefit Assessment 
In light of the above discussions, the risk-benefit ratio is favorable and justifies proceeding 
with this research.  


 
  
 
 
 
37 
8.5 Recruitment Strategy 
Potential subjects will have already completed their clinical evaluation by otolaryngology at 
any of our outpatient clinics, and the decision for surgery (tonsillectomy with or without 
adenoidectomy) will have already been made.  During the same visit, the pre-operative nurse 
practitioner (NP) history and physical will have already been performed as part of standard 
clinical care.  This NP will notify the study staff of the potential subject.  At this point, a 
member of the study staff will approach potentially eligible subjects to explain the study and 
determine if the family is interested in enrolling.  Interested families then proceed with the 
remainder of the procedures listed under Screening Visit, above.  Informed consent is then 
obtained as per the next section.  This pre-operative clinic visit is anywhere from 2 days to 
several months before surgery, but is most typically 2-6 weeks prior to the procedure date. 
It is possible some potential subjects will be interested in the study, but will be unable to 
complete screening procedures on the same day as the preoperative clinic visit.  An example 
might be subjects recruited from clinic visits at the CHOP Specialty Care Centers, where a 
Study Team Member is not immediately available.  These subjects will be given a blank 
consent document, with instructions to read it at home.  They will receive a telephone call 
from a member of the Study Team within the next few days.  The Team member will 
explain the research study in detail, answer any questions, and perform screening procedures 
as indicated above.  A time will then be arranged to perform the Informed Consent process 
below, electronically or in person, before the scheduled surgery.  
8.6 Informed Consent/Assent and HIPAA Authorization 
At the end of the pre-operative clinic visit, a member of the study staff screens interested 
patients and reviews inclusion and exclusion criteria as described in the Screening Visit 
section.  The study and its risks are explained to the subject and family and informed 
consent (and assent, if applicable) is obtained.  An otolaryngology physician will be 
immediately available to answer any questions about the study procedures or risks. The 
family is then given a copy of the Informed Consent document at the end of the visit.  This 
document is a combined consent/assent and HIPAA authorization.  These discussions occur 
in a private room in the outpatient clinic. 
For the subjects described in Section 8.5, who were unable to perform the Informed Consent 
process at the clinic visit, the following will occur.  A Study Team member will telephone 
the potential subject well ahead of the surgery day, explain the study to them, and perform 
screening assessments as described above.  The actual Informed Consent/Assent process 
will occur as follows.  For those subjects who are scheduled for any visit to Main Campus 
prior to the surgery date, consent/assent will simply be obtained in person at that visit.  An 
otolaryngology physician will be immediately available by telephone to answer any 
questions about the study procedures or risks.  The family is then given a copy of the 
Informed Consent document at the end of that visit. 
For the remaining subjects not coming to Main Campus prior to surgery, an electronic/ 
remote written consent process will be implemented, following FDA guidelines.  For any 
subject who does not yet have the consent form, or lost it, it will first be sent to them by 
facsimile, e-mail, or mail.  The consent interview is then conducted by telephone when the 


 
  
 
 
 
38 
parent can read the consent form during the discussion (and when the child is available for 
assent, if applicable). After the consent discussion, the parent (and child, if applicable) will 
sign and date the consent form and return the entire consent form to us by facsimile, by 
scanning and sending via a secure e-mail account, or by mail.  This team member obtaining 
consent will document in REDCap that the person signing the document is the subject/parent 
who will be participating in the research.  The parent will have the opportunity to ask 
questions and receive answers prior to signing the form.   An otolaryngology physician will 
either be immediately available during the call to answer any questions about the study 
procedures or risks, or the parent will be given a description of how and when they will 
receive answers to their questions (usually by a telephone call later from the physician).  The 
family keeps their copy of the signed Informed Consent document.  Upon receipt, the team 
member who obtained the remote consent will then file the complete document, after first 
signing and dating the signature pages.  If the child is 7 or older and cannot be present 
during the phone call, assent will be documented on the ICF on the day of surgery, before 
any study procedures occur.   
Regardless of method of obtaining consent, subjects will be instructed to not sign the 
document until all questions they have for a physician are answered.  Subjects are counseled 
that they may freely choose not to participate in the study, but if so, they will not receive 
celecoxib. They will be informed that this will not otherwise affect their other medical care 
or treatment.  In particular, it will be emphasized that their pain control would follow 
standard of care outside the study, and that they will still obtain the recommended surgery in 
the usual fashion.  Families are given as much time as they need to make their decision and 
ask questions of the staff and physician, who will ensure that subjects comprehend the 
nature of the study, the study procedures and the risks and benefits of participation before 
providing consent. 
8.7 Payment to Subjects/Families 
8.7.1 Reimbursement for travel, parking and meals 
Not applicable.  There are no study visits separate from clinical care. 
8.7.2 Payments to parent for time and inconvenience (i.e. compensation) 
Parents who complete all study procedures and return their Study Diary will receive a 
$25.00 gift card.  This incentive is critical to the success of the study, as in prior 
tonsillectomy studies we have found poor compliance rates with completing/ returning 
diaries when no incentive is offered.  This is especially important in this study design, since 
subjects do not routinely return for any visits postoperatively, and must complete these 
materials at home, and mail them back to us.   This is an inconvenience to parents, who must 
perform extra work at home (completing Diaries, measuring pain, logging doses of pain 
medication, and mailing the Diary back) during an often difficult and painful postoperative 
recovery period. 
8.7.3 Payments to subject for time, effort and inconvenience (i.e. compensation) 
No payment to subjects themselves.  Because the side effects of study drug are expected to 
be minimal, the hardship, effort, and inconvenience for the pediatric subjects are similar as 
outside the research. 


 
  
 
 
 
39 
8.7.4 Gifts 
Not applicable. 
9 
PUBLICATION 
Results of this research will be presented at national meetings and will be published in 
relevant journals.  Appropriate disclosure will be made that the research was conducted 
under off-label use of the study medication. 
 
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Giordano T, Litman RS, Li KK, Mannix ME, Schwartz RH, Setzen G, Wald ER, Wall 
E, Sandberg G, Patel MM.  Clinical practice guideline: tonsillectomy in children. 
Otolaryngol Head Neck Surg. 2011;144:S1-30. 
Cardwell ME, Siviter G, Smith AF.  Non-steroidal anti-inflammatory drugs and 
perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 
2005;(2):CD003591. 
Derry S, Moore R. Single dose oral celecoxib for acute postoperative pain in adults. 
Cochrane Database Syst Rev 2013;10:CD004233. 
Donnelly RF, Pascuet E, Ma C, Vaillancourt R. Stability of celecoxib oral suspension. Can J 
Hosp Pharm. 2009;62:464-8. 
Foeldvari I, Szer I, Zemel L, et al. A Prospective Study Comparing Celecoxib with 
Naproxen in Children with Juvenile Rheumatoid Arthritis. J Rheumatol 2009;36:174-
182. 
Hippisly-Cox J, Coupland C, Logan R.  Risk of adverse gastrointestinal outcomes in patients 
taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory 
drugs: population based nested case-control analysis.  BMJ 2005; 331:1310-1316. 
Joshi W, Connelly NR, Reuben SS, Wolckenhaar M, Thakkar N. An evaluation of the safety 
and efficacy of administering rofecoxib for postoperative pain management. Anesth 
Analg. 2003;97:35-8. 
Krishna S, Hughes LF, Lin SY.  Postoperative hemorrhage with nonsteroidal anti-
inflammatory drug use after tonsillectomy: a meta-analysis. Arch Otolaryngol Head 
Neck Surg. 2003;129:1086-1089. 
Krishnaswami S1, Hutmacher MM, Robbins JL, Bello A, West C, Bloom BJ.  Dosing 
celecoxib in pediatric patients with juvenile rheumatoid arthritis.  J Clin Pharmacol. 
2012;52:1134-49.  
Kuehn BM.  FDA: No Codeine After Tonsillectomy for Children. JAMA. 
2013;309(11):1100. 
Lesko SM, Mitchell AA. Renal function after short-term ibuprofen use in infants and 
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APPENDIX 
 
1. Wong-Baker FACES scale for estimating pain level in children 3 and older [Wong 
and Baker 1988]. 
 
 
 
 
 
2. Ten-point Pain Scale for estimating pain level in older children (ages 10 and above). 
 
 
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