Clinical trial NCT01605903
Conditions: Tonsillectomy Adenoidectomy
Keywords: Tonsillectomy adenoidectomy bleeding bleeding rates Tonsillectomy with and without adenoidectomy
Sponsor: Massachusetts Eye and Ear Infirmary
Start date: 2012-05-03; Completion date: 2017-02-15
Enrollment: 741 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tonsillectomy (the surgical removal of the tonsils) is a commonly performed surgery in children. One risk of tonsillectomy is postoperative bleeding, and this can be more dangerous in children because their blood volume is lower than adults. Ibuprofen, a nonsteroidal anti-inflammatory medication (NSAID), is an effective pain medication. Recent guidelines, published by the American Academy of Otolaryngology, advocated use of ibuprofen after tonsillectomy. However, NSAIDs are associated with altered platelet function and a theoretical increased risk of bleeding after surgery. The investigators would like to explore the effect that ibuprofen has on postoperative bleeding, as well as validate previous studies demonstrating it is an effective pain medication after tonsillectomy.

Detailed description:
Tonsillectomy with and without adenoidectomy is one of the most commonly performed surgical procedures in the pediatric population. The incidence of adenotonsillectomy has increased over the past four decades (1). This is mainly due to increased awareness of the potential adverse consequences that pediatric sleep disordered breathing (SDB) may have on development and long-term pulmonary and cardiovascular health. SDB has surpassed recurrent tonsillitis as the most common indication for adenotonsillectomy in children (2-5). Over the past decade, according to the CDC's National Health Statistic Report on ambulatory surgery performed in the US, annual rates of tonsillectomy performed with and without adenoidectomy in children aged 15 and younger increased from 287,000 to 530,000 (6, 7). Adenotonsillectomy is the second most common procedure performed on children under the age of 15. Although generally considered a safe procedure, adenotonsillectomy has significant morbidity and potential for complications, particularly in the pediatric population. Complications include postoperative hemorrhage, dehydration, pain, anesthetic complications and airway risks, aspiration, and post-obstructive pulmonary edema (8). In young children, the risk of adenotonsillectomy is more critical due to smaller airways and respiratory reserve, as well as smaller blood volume (5).

Postoperative bleeding can be categorized as a primary event, occurring \< 24 hours after surgery, or a secondary event, occurring \>24 hours after tonsillectomy. Additionally, events can be further described by the interventions taken, such as emergency room visits, admission for observation, or return to the operating room to achieve hemostasis. Postoperative bleeding rates, including both primary and secondary events, range from 3.3-20%, with a mean of 4.5% (9). Thus, annually, tens of thousands of children experience exposure to potentially life-threatening postoperative hemorrhage, often requiring readmission, anesthetic exposure, and operative control of hemorrhage.

Postoperative pain contributes significantly to post-tonsillectomy morbidity. While narcotics are effective in controlling postoperative pain, they are often contraindicated, particularly in children with sleep disordered breathing, because of their potentially adverse side effects on respiration and the central nervous system (10). Nonsteroidal anti-inflammatories (NSAIDS), which block prostaglandin-induced inflammation and edema, are an attractive therapeutic option because they do not result in respiratory and central nervous system depression, and therefore may reduce the risk of postoperative respiratory depression, nausea and vomiting, excessive sedation and urinary retention. NSAIDS have been shown to be effective analgesics after tonsillectomy (11,12). However, because their mechanism of action may also interfere with platelet aggregation and increase bleeding time, their use is balanced with concern about an increased risk of postoperative hemorrhage. Aspirin, which irreversibly inhibits cyclooxygenase, affects coagulation and bleeding for up to 10 days, has been associated with an increased bleed rate after tonsillectomy (13). However, non-aspirin NSAIDs demonstrate a reversible inhibition of COX-1 and COX-2, and therefore do not have the same severe, prolonged effects on bleeding (14). Ibuprofen, a derivative of propionic acid, is widely used for musculoskeletal pain, but the study of its use for post-tonsillectomy analgesia is limited.

In 2011, The American Academy of Otolaryngology published Clinical Practice Guidelines outlining evidence-based selection and perioperative management strategies for tonsillectomy in children. As part of a recommendation that clinicians educate caregivers about the importance of postoperative pain management, Baugh et al advocated the use of ibuprofen postoperatively, stating, "ibuprofen can be used safely for pain control after surgery" (15), citing a 2005 Cochrane Review of NSAIDs and post-tonsillectomy bleeding in support of this guideline (16). The Cochrane Review recently added additional studies to their analysis and results remained similar. The most recent Cochrane Review, published in 2010, evaluated 15 randomized trials comparing NSAIDs with other analgesics or placebo, and determined that NSAID use did not significantly alter the number of perioperative bleeding episodes, both requiring and not requiring surgical intervention; this review did not distinguish between primary and secondary bleeding events (17). Because post-tonsillectomy hemorrhage is an uncommon event, a large number of participants is required to provide an adequate number of events to give a significant result, therefore the large sample size of \>1000 children in the Cochrane Review is admirable. However, sample sizes were not adequate to compare the risk of bleeding with each individual NSAID. Additionally, NSAIDs were given in both oral and parenteral forms, as well as preoperatively, intraoperatively and postoperatively, and the duration of postoperative analgesic use differed between studies. The surgical technique used was not uniform between studies as well. It is our feeling that because of these limitations, the data is not sufficient to broadly implement the Academy's recommendation that ibuprofen can be safely used for post-tonsillectomy analgesia without more carefully controlled, prospective study.

Although there are many studies in the literature evaluating NSAID use after tonsillectomy, there are few randomized-prospective trials evaluating the use of ibuprofen, and few trials are powered to adequately assess the risk of postoperative hemorrhage. Designing and executing a study to specifically evaluate ibuprofen after pediatric tonsillectomy and rates of post-operative hemorrhage requiring return to the operating room for control is important to the pediatric otolaryngology community, particularly given the American Academy of Otolaryngology's recent clinical guidelines. The results of such a definitive study would possibly affect the tens of thousands of children at risk for post-tonsillectomy hemorrhage every year. It would affect our own standards of care as well as national and international norms.

Preliminary Studies:

At the Massachusetts Eye and Ear Infirmary there is no precedent for administering ibuprofen to children after tonsillectomy with or without adenoidectomy. Despite American Academy of Otolaryngology support for the use of ibuprofen in the postoperative setting, pediatric otolaryngologists at our institution are still hesitant to administer ibuprofen postoperatively without additional study of its use.

Within the Department of Pediatric Otolaryngology at the Massachusetts Eye and Ear Infirmary there is a precedent for successful completion of randomized, controlled trials involving adenotonsillectomy (19, 20). With principal investigators dedicated to clinical research, as well as research nurses and coordinators at our disposal, a prospective, controlled clinical trial of ibuprofen use after tonsillectomy can be implemented. Additionally, the Massachusetts Eye and Ear Infirmary calculates annual post-tonsillectomy hemorrhage rates, including percentage of patients returning to the emergency room for evaluation for possible post-operative bleeding, as well as the percentage of patients returning to the operating room for control of bleeding. Thus, there is a precedent for collecting data on postoperative bleeding events, as well as a controlled bleed rate to which prospective study hemorrhage rates can be compared.

The goal of our study is to determine if postoperative ibuprofen affects the rate of post-tonsillectomy hemorrhage using a non-inferiority trial design, which is intended to show that the effect of ibuprofen is no worse than acetaminophen, which will serve as our control. This differs from an equivalence trial, which aims to demonstrate that the experimental and control group do not differ more than a specified amount. The equivalence margin set for non-inferiority trials is often smaller than the treatment difference for which a placebo-controlled trial is powered, requiring a larger sample size. This will address two issues we have with the current literature evaluating NSAID use after tonsillectomy: inadequate sample size, and unrealistic treatment differences, including up to a 20% difference in bleed rates, required to detect a significant difference between NSAID and control groups. Because our trial will be designed to test non-inferiority, the null hypothesis will assume inferiority: the rate of hemorrhage requiring operative intervention in patients treated with postoperative ibuprofen after tonsillectomy will be increased compared to the rate in patients given acetaminophen.

Arms: arm 1: Children in the experimental group will receive grape-flavored ibuprofen 100mg/5 mL. Ibuprofen will be dispensed at 10mg/kg (max dose 600 mg) will be dispensed Q6 hours x 9 days. arm 2: Children in the active comparator group will receive grape flavored acetaminophen 160 mg/5 ml. Acetaminophen will be dispensed at 15 mg/kg (max dose 650/mg) Q6 hours x 9 days.
Interventions: intervention 1: Ibuprofen intervention 2: Acetaminophen
Intervention descriptions: intervention 1: Children in the ibuprofen group will be receive grape-flavored ibuprofen 100mg/5 mL. During the postoperative period, ibuprofen 10mg/kg (max dose 600 mg) will be dispensed Q6. intervention 2: During the postoperative period, ibuprofen 10mg/kg (max dose 600 mg) will be dispensed Q6.

Protocol documents:
Prot_001.pdf: 
Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Last Updated: 02-Dec-2010 
1 
Form I - Protocol Application 
IRBNet ID: 
242942-1 
HSC Protocol #: 
Principal Investigator Name: Christopher Hartnick, MD 
Date: 
6/1/2016 
Project Title: 
Postoperative Ibuprofen and the Risk of Bleeding After Tonsillectomy with or 
without Adenoidectomy 
Funding Source: 
Intradepartmental Funds 
*To mark a ‘check’ box, click on the item you would like to select and type an ‘x’. For all 
other questions, click on the area below the question to type your response. 
The Core Data Form needs to be completed online and submitted along this application. 
This form must be filled out completely. Do not leave any sections blank. If a field does 
not apply to your research state so using the abbreviation “NA”. For any items described 
in the sponsor’s protocol or other documents submitted with the application, you may 
reference the title and page numbers of these documents. If you reference page numbers, 
attach those pages to this protocol application package. Limit attached pages to those 
referenced in this protocol. 
1a. Collaborating Institution(s): Please list any institution involved in the study and the status 
of IRB approval. 
Medical Center, Naval Medical Center, Portsmouth, VA. 
Madigan Army Base, Naval Medical Center of San Diego, Brooke Army 
Response: 
1b. Where will the study take place? Please list all locations outside of 243 Charles street 
where human subjects research related to this study is expected to occur. 
Response: Madigan Army Base; Tacoma, WA; Naval Medical Center of San Diego, 
Department of Otolaryngology; San Diego, CA; Brooke Army Medical Center, Department of 
Otolaryngology; San Antonio, TX; Naval Medical Center, Department of Otolaryngology; 
Portsmouth, VA. 
2. In layperson’s language please state the purpose of this study in 3-5 sentences. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
Response: 
Tonsillectomy (the surgical removal of the tonsils) is a commonly performed 
surgery in children. One risk of tonsillectomy is postoperative bleeding, and this can be more 
dangerous in children because their blood volume is lower than adults. Ibuprofen, a nonsteroidal 
anti-inflammatory medication (NSAID), is an effective pain medication. Recent guidelines, 
published by the American Academy of Otolaryngology, advocated use of ibuprofen after 
tonsillectomy. However, NSAIDs are associated with altered platelet function and a theoretical 
increased risk of bleeding after surgery. We would like to explore the effect that ibuprofen has 
on postoperative bleeding, as well as validate previous studies demonstrating it is an effective 
pain medication after tonsillectomy. 
SPECIFIC AIM 
 
Response: 
Specific Aim 1: To compare the rates of post-tonsillectomy bleeding between 
pediatric patients who receive postoperative ibuprofen to those who receive acetaminophen in a 
prospective, randomized, blinded and controlled trial. 
 
The primary objective of this study is to determine if postoperative ibuprofen at 10mg/kg dosing 
four times daily postoperatively for 9 days is associated with an increased rate of post- 
tonsillectomy bleeding requiring operative intervention for hemostasis in children when 
compared with acetaminophen. To achieve this, rates of post-tonsillectomy bleeding, both 
primary, defined as occurring < 24 hours after surgery, and secondary, defined as occurring > 24 
hours after tonsillectomy, will be recorded. Additionally, distinction will be made between 
bleeds requiring emergency room evaluation, admission for observation, and operative control of 
hemorrhage. 
 
Specific Aim 2: To compare the rates of post-tonsillectomy hemorrhage when studying different 
groups of patients based upon their age, indication for tonsillectomy, or operating surgeon. 
 
The second objective of this study is to determine if bleeding rates differ according to surgical 
indication, age of the patient, or operating surgeon, using a multi-variate logistic regression 
model. This is important since indication for tonsillectomy varies in children. Younger children 
tend to undergo tonsillectomy for obstructive sleep symptoms whereas older children tend to 
undergo tonsillectomy for infectious tonsillitis. 
 
Specific Aim 3: To evaluate effectiveness of ibuprofen as a post-tonsillectomy analgesic in 
comparison to Acetaminophen, which is currently the standard of care at our institution. 
 
The third objective of this study is to evaluate the efficacy of ibuprofen at 10mg/kg dosing (max 
dose 600mg) at Q6 hour dosing as an analgesic in the postoperative period in comparison to 
Acetaminophen, 15mg/kg (max dose 650mg), which is currently the standard of care at our 
institution. Previous studies have determined that ibuprofen at 5mg/kg dosing is an effective 
 
2 
Last Updated: 26-Apr-2011 
3. Please state the specific aims of the research being proposed and the hypothesis which you 
will be testing. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
post-tonsillectomy analgesic, however 10mg/kg dosing, the maximum ibuprofen dose, has not 
been previously evaluated in the literature. We feel it is important to evaluate both the analgesic 
effect and rate of post-tonsillectomy bleeding associated with this maximum dosing if ibuprofen 
is to be widely used in the postoperative period after tonsillectomy. 
 
 
BACKGROUND 
 
Response: 
Tonsillectomy with and without adenoidectomy is one of the most commonly 
performed surgical procedures in the pediatric population. The incidence of adenotonsillectomy 
has increased over the past four decades (1). This is mainly due to increased awareness of the 
potential adverse consequences that pediatric sleep disordered breathing (SDB) may have on 
development and long-term pulmonary and cardiovascular health. SDB has surpassed recurrent 
tonsillitis as the most common indication for adenotonsillectomy in children (2-5). Over the past 
decade, according to the CDC’s National Health Statistic Report on ambulatory surgery 
performed in the US, annual rates of tonsillectomy performed with and without adenoidectomy 
in children aged 15 and younger increased from 287,000 to 530,000 (6, 7). Adenotonsillectomy 
is the second most common procedure performed on children under the age of 15. Although 
generally considered a safe procedure, adenotonsillectomy has significant morbidity and 
potential for complications, particularly in the pediatric population. Complications include 
postoperative hemorrhage, dehydration, pain, anesthetic complications and airway risks, 
aspiration, and post-obstructive pulmonary edema (8). In young children, the risk of 
adenotonsillectomy is more critical due to smaller airways and respiratory reserve, as well as 
smaller blood volume (5). 
 
Postoperative bleeding can be categorized as a primary event, occurring < 24 hours after surgery, 
or a secondary event, occurring >24 hours after tonsillectomy. Additionally, events can be 
further described by the interventions taken, such as emergency room visits, admission for 
observation, or return to the operating room to achieve hemostasis. Postoperative bleeding rates, 
including both primary and secondary events, range from 3.3-20%, with a mean of 4.5% (9). 
Thus, annually, tens of thousands of children experience exposure to potentially life-threatening 
postoperative hemorrhage, often requiring readmission, anesthetic exposure, and operative 
control of hemorrhage. 
 
Postoperative pain contributes significantly to post-tonsillectomy morbidity. While narcotics are 
effective in controlling postoperative pain, they are often contraindicated, particularly in children 
with sleep disordered breathing, because of their potentially adverse side effects on respiration 
and the central nervous system (10). Nonsteroidal anti-inflammatories (NSAIDS), which block 
prostaglandin-induced inflammation and edema, are an attractive therapeutic option because they 
do not result in respiratory and central nervous system depression, and therefore may reduce the 
risk of postoperative respiratory depression, nausea and vomiting, excessive sedation and urinary 
retention. NSAIDS have been shown to be effective analgesics after tonsillectomy (11,12). 
 
3 
Last Updated: 26-Apr-2011 
4. Summarize the background, nature, rationale (include any previous or ongoing related HSC 
protocol #’s) and the significance of the proposed study. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
However, because their mechanism of action may also interfere with platelet aggregation and 
increase bleeding time, their use is balanced with concern about an increased risk of 
postoperative hemorrhage. Aspirin, which irreversibly inhibits cyclooxygenase, affects 
coagulation and bleeding for up to 10 days, has been associated with an increased bleed rate after 
tonsillectomy (13). However, non-aspirin NSAIDs demonstrate a reversible inhibition of COX-1 
and COX-2, and therefore do not have the same severe, prolonged effects on bleeding (14). 
Ibuprofen, a derivative of propionic acid, is widely used for musculoskeletal pain, but the study 
of its use for post-tonsillectomy analgesia is limited. 
 
In 2011, The American Academy of Otolaryngology published Clinical Practice Guidelines 
outlining evidence-based selection and perioperative management strategies for tonsillectomy in 
children. As part of a recommendation that clinicians educate caregivers about the importance of 
postoperative pain management, Baugh et al advocated the use of ibuprofen postoperatively, 
stating, “ibuprofen can be used safely for pain control after surgery” (15), citing a 2005 
Cochrane Review of NSAIDs and post-tonsillectomy bleeding in support of this guideline (16). 
The Cochrane Review recently added additional studies to their analysis and results remained 
similar. The most recent Cochrane Review, published in 2010, evaluated 15 randomized trials 
comparing NSAIDs with other analgesics or placebo, and determined that NSAID use did not 
significantly alter the number of perioperative bleeding episodes, both requiring and not 
requiring surgical intervention; this review did not distinguish between primary and secondary 
bleeding events (17). Because post-tonsillectomy hemorrhage is an uncommon event, a large 
number of participants is required to provide an adequate number of events to give a significant 
result, therefore the large sample size of >1000 children in the Cochrane Review is admirable. 
However, sample sizes were not adequate to compare the risk of bleeding with each individual 
NSAID. Additionally, NSAIDs were given in both oral and parenteral forms, as well as 
preoperatively, intraoperatively and postoperatively, and the duration of postoperative analgesic 
use differed between studies. The surgical technique used was not uniform between studies as 
well. It is our feeling that because of these limitations, the data is not sufficient to broadly 
implement the Academy’s recommendation that ibuprofen can be safely used for post- 
tonsillectomy analgesia without more carefully controlled, prospective study. 
 
Although there are many studies in the literature evaluating NSAID use after tonsillectomy, there 
are few randomized-prospective trials evaluating the use of ibuprofen, and few trials are powered 
to adequately assess the risk of postoperative hemorrhage. Designing and executing a study to 
specifically evaluate ibuprofen after pediatric tonsillectomy and rates of post-operative 
hemorrhage requiring return to the operating room for control is important to the pediatric 
otolaryngology community, particularly given the American Academy of Otolaryngology’s 
recent clinical guidelines. The results of such a definitive study would possibly affect the tens of 
thousands of children at risk for post-tonsillectomy hemorrhage every year. It would affect our 
own standards of care as well as national and international norms. 
 
Preliminary Studies: 
At the Massachusetts Eye and Ear Infirmary there is no precedent for administering ibuprofen to 
children after tonsillectomy with or without adenoidectomy. Despite American Academy of 
Otolaryngology support for the use of ibuprofen in the postoperative setting, pediatric 
 
 
4 
Last Updated: 26-Apr-2011 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
otolaryngologists at our institution are still hesitant to administer ibuprofen postoperatively 
without additional study of its use. 
 
Within the Department of Pediatric Otolaryngology at the Massachusetts Eye and Ear Infirmary 
there is a precedent for successful completion of randomized, controlled trials involving 
adenotonsillectomy (19, 20). With principal investigators dedicated to clinical research, as well 
as research nurses and coordinators at our disposal, a prospective, controlled clinical trial of 
ibuprofen use after tonsillectomy can be implemented. Additionally, the Massachusetts Eye and 
Ear Infirmary calculates annual post-tonsillectomy hemorrhage rates, including percentage of 
patients returning to the emergency room for evaluation for possible post-operative bleeding, as 
well as the percentage of patients returning to the operating room for control of bleeding. Thus, 
there is a precedent for collecting data on postoperative bleeding events, as well as a controlled 
bleed rate to which prospective study hemorrhage rates can be compared. 
 
The goal of our study is to determine if postoperative ibuprofen affects the rate of post- 
tonsillectomy hemorrhage using a non-inferiority trial design, which is intended to show 
that the effect of ibuprofen is no worse than acetaminophen, which will serve as our 
control. This differs from an equivalence trial, which aims to demonstrate that the 
experimental and control group do not differ more than a specified amount. The 
equivalence margin set for non-inferiority trials is often smaller than the treatment 
difference for which a placebo-controlled trial is powered, requiring a larger sample size. 
This will address two issues we have with the current literature evaluating NSAID use after 
tonsillectomy: inadequate sample size, and unrealistic treatment differences, including up 
to a 20% difference in bleed rates, required to detect a significant difference between 
NSAID and control groups. Because our trial will be designed to test non-inferiority, the 
null hypothesis will assume inferiority: the rate of hemorrhage requiring operative 
intervention in patients treated with postoperative ibuprofen after tonsillectomy will be 
increased compared to the rate in patients given acetaminophen. 
 
References: 
1. Erickson BK, Larson DR, St Sauver JL, Meverden RA, Orvidas LJ. Changes in incidence and 
indications of tonsillectomy and adenotonsillectomy, 1970-2005. 
2. Bluestone CD. Current indications for tonsillectomy and adenoidectomy. Ann Otol Rhinol 
Laryngol Suppl 1992; 155:58-64. 
3. Berkowitz RG, Zalzal GH. Tonsillectomy in children under 3 years of age. Arch Otolaryngol 
Head Neck Surg 1990; 116:685-6. 
4. Tom LWC, DeDio RM, Cohen DE, et al. Is outpatient tonsillectomy appropriate for young 
children? Laryngoscope 1992; 102:277-80. 
5. Ross AT, Kazahaya K, Tom LW. Revisiting outpatient tonsillectomy in young children. 
Otolaryngol Head Neck Surg 2003; 128:326-31. 
6. National Center for Health Statistics, Centers for Disease Control, Advance data 283: 
ambulatory surgery in the United States, 1994. National Center for Health Statistics. Available 
on the Web at www.cdc.gov/nchs. 
 
 
 
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Last Updated: 26-Apr-2011 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
7. National Health Statistics Reports, Centers for Disease Control, Ambulatory Surgery in the 
United States, 2006. Number 11, January 28, 2009–Revised September 4, 2009. Available on 
the Web at www.cdc.gov/nchs. 
8. Randall DA, Hoffer ME. Complications of tonsillectomy and adenoidectomy. Otolaryngol 
Head Neck Surg. 1998; 118:61-8. 
9. Blakley BW. Post-tonsillectomy bleeding: How much is too much? Otolaryngol Head Neck 
Surg 2009; 140:288-290. 
10. Huasband AD, Davis A. Pain after tonsillectomy. Clin Otolaryngol 1996; 21: 99-101. 
11. Harley EH, Dattolo RA. Ibuprofen for tonsillectomy pain in children: Efficacy and 
complications. Otolaryngol Head Neck Surgy 1998; 119(5): 492-496. 
12. St. Charles CS, Matt BH, Hamilton MM, Katz BP. A comparison of ibuprofen 
versus acetaminophen with codeine in the young tonsillectomy patient. Otolaryngol Head Neck 
Surg 1997; 117(1): 76-82. 
13. Reuter SH, Montgomery WW. Aspirin vs acetaminophen after tonsillectomy. Arch 
Otolaryngol Head Neck Surg 1964; 80: 214-17. 
14. Schaefer AI. Effects of nonsteroidal anti-inflammatory drugs on platelet function and 
systemic hemostasis. J Clin Pharmacol 1995; 35: 209-19. 
15. Baugh RF, Archer SM, Mitchell RB, Rosenfeld RM et al. Clinical practice guideline: 
tonsillectomy in children. Otolaryngol Head Neck Surg 2011: 144(IS): S1-S30. 
16. Cardwell ME, Siviter G, Smith AF. Non-steroidal anti-inflammatory drugs and 
perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2005; (2): 
CD003591. 
17. Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti-inflammatory drugs and perioperative 
bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2010; (10): CD 
18. Brigger MT, Cunningham MJ, Hartnick CJ. Dexamethasone administration and 
postoperative bleeding risk in children undergoing tonsillectomy. Arch Otolaryngol Head Neck 
Surg 2010; 136(8): 766-72. 
19. Lister MT, Cunningham MJ, Williams BB, Tirell A, Schaumberg DA, Hartnick CJ. 
Microdebrider tonsillotomy vs electrosurgical tonsillectomy: a randomized, double-blind, paired 
control study of postoperative pain. Arch Otolaryngol Head Neck Surg 2006; 132(6): 599-604. 
20. Collison PJ, Mettler B. Factors associated with post-tonsillectomy hemorrhage. Ear Nose 
Throat 2000; 79(8): 641-49. 
 
 
RESEARCH PLAN 
 
Response: 
 
Recruitment: Patients will be recruited from the practices of Drs. Hartnick, Keamy, Setlur and 
Cohen, as well as Dr. Diercks starting September 1, 2016 (The Massachusetts Eye and Ear 
 
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5. Provide an orderly description of the study design and research procedures including a list 
of assessments at each visit. If you are using a placebo, please provide justification. If this is a 
clinical trial, please attach a flow chart or schema to this application package. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
Infirmary), Drs. Boseley and Rogers (Madigan Army Base; Tacoma, WA), Brigger and 
Gaudreau (Naval Medical Center of San Diego, Department of Otolaryngology; San Diego, CA), 
Maturo (Brooke Army Medical Center, Department of Otolaryngology; San Antonio, TX), and 
Gallagher (Naval Medical Center, Department of Otolaryngology; Portsmouth, VA). Over the 
last two years, the average annual number of pediatric tonsillectomies for each collaborating 
investigator was approximately 200. Informed consent will be obtained for the study by the 
principal investigator, co-investigators, or research nurses at the time of the preoperative visit or 
on the day of surgery prior to arrival in the preoperative area. 
 
Inclusion criteria: Patients ages 2-18 undergoing tonsillectomy with or without adenoidectomy 
by electrocautery alone for sleep disordered breathing or infectious tonsillitis. Patients with 
complex medical conditions and craniofacial abnormalities will be included. Only patients who 
are not pregnant will be included. Informed consent and child assent will be required for 
enrollment. 
 
Exclusion criteria: Patients with a known personal or family history of a bleeding disorder will 
be excluded. Patients with a history of asthma, kidney or liver problems will also be excluded. 
Patients with tonsillectomy or adenoidectomy performed using a cold knife technique, 
microdebrider, coblation or plasma knife. Patients on NSAIDs for other medical conditions, or 
those who have taken NSAIDs within 1 week of surgery will be excluded. 
Patients with allergy 
to aspirin or other NSAIDs, acetaminophen, Red Dye #40 or Red Dye #33 will also be excluded. 
Pregnancy testing using urine beta-HCG will be performed on all children > 13 years of age, or 
those younger than 13 who are menstruating; this is the testing protocol used at the Children’s 
Hospital of Boston. Patients found to be pregnant will be excluded from participation. Patients 
unwilling to enroll in the study will have the tonsillectomy with or without adenoidectomy 
performed according to current practice standards. 
 
Randomization: Patients will be randomized upon enrollment after obtaining informed consent, 
and assent when indicated. Randomization will be performed centrally by the pharmacy of 
Massachusetts Eye and Ear Infirmary for all participating institutions. Randomization will occur 
via a one-to-one scheme. Randomization will be generated based on a uniform (0,1) random 
number generator using STATA code. 
 
Blinding: The surgeon, nurses, and patient/parent will be blinded regarding to which arm the 
patient has been randomized. The pharmacy of each institution will dispense grape-flavored 
ibuprofen 100mg/5mL (Leader) or grape-flavored acetaminophen 160mg/5mL (Leader) 
based upon the arm to which each participant has been randomized. Ibuprofen will be dosed at 
10mg/kg (max dose 600mg) and acetaminophen at 15mg/kg (max dose 650mg), dosing for each 
will be QID, or roughly Q6 hours when appropriate. The pharmacy will manipulate the volume 
of each medication using Ora Blend suspension so that for each child, weight based dosing of 
each medication will be equivalent in volume. Medications will be dispensed an amber colored 
bottle with a syringe to measure and dispense the appropriate weight based volume of each 
medication. Each bottle will specify the patient’s name, medical record number, and the volume 
of medication to be dispense during each medication administration. This supply of medication 
will be used to dispense analgesics both while the patient is hospitalized, and upon discharge for 
the first 8 postoperative days. 
 
7 
Last Updated: 26-Apr-2011 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
Surgical technique: All patients will be administered 15mg/kg (max dose 650mg) of 
acetaminophen preoperatively prior to arrival in the preoperative area and dexamethasone 
0.5mg/kg (maximum dose of 8mg) in the operating room prior to surgical commencement, 
which is standard practice at MEEI. The standard method of tonsillectomy among participating 
surgeons will be extracapsular monopolar electrocautery with standard settings of 12 watts 
(fulgurate) using a spatula tip. Bleeding will be controlled with suction cautery on a setting of 
12-18 watts (fulgurate). Adenoidectomy will be performed at 30 watts (fulgurate). Anesthetic 
technique, perioperative analgesia with narcotics, and post-operative care will remain equivalent 
between the two study arms. Antibiotics will not be administered in the perioperative period. 
Postoperative anti-emetic therapy will be standardized by all collaborating physicians using 
standardized order sets. 
 
Postoperative period: Postoperative antibiotics will not be administered based upon the 
American Academy of Otolaryngology’s strong recommendation that antibiotics no longer be 
used for postoperative prophylaxis after adenotonsillectomy (15). For the first 8 postoperative 
days (9 days total, POD0-9), children will be administered weight based analgesia from 
medication provided by the inpatient pharmacy at MEEI four times daily while awake (roughly 
Q6 hour dosing). Medication will be administered from an amber colored bottle containing 36 
doses of medication (QID dosing x 9 total days), which will be labeled with the child’s name, 
medical record number, and dosing instructions. The volume of medication dispensed for each 
child will be manipulated with OraBlend solution such that the weight based dose of ibuprofen 
volume will equal the weight based dose of acetaminophen volume; both medications will be 
dosed QID. Surgeons, nursing staff, and patients and their families will be blinded regarding the 
type of medication administered (acetaminophen vs. ibuprofen). Acetaminophen will be given 
as 15mg/kg dosing (maximum dose 650mg) and ibuprofen will be given as 10mg/kg dosing 
(maximum dose 600mg). Children with breakthrough pain eligible for narcotics (based upon 
age, OSA status) will receive weight based doses of oxycodone 1mg/1mL elixir (0.05-0.1mg/kg) 
as well as be prescribed oxycodone to use for breakthrough pain as an outpatient. After 9 days, 
patients will be instructed to take acetaminophen 15mg/kg (max dose 650mg) every 4-6 hours as 
needed for breakthrough pain. They will be instructed not to use nonsteroidal anti-inflammatory 
drugs (NSAIDS) in the postoperative period (14 days). 
 
Weight based ibuprofen dosing of 10mg/kg was chosen because it is the maximum dose of this 
medication. Previous studies evaluating ibuprofen use after tonsillectomy used ibuprofen at 
5mg/kg (11,12). If ibuprofen is to be used for post-tonsillectomy analgesia, it would likely be 
used at the maximum dose, similar to the maximum dose of Acetaminophen (15mg/kg) already 
used in standard practice at our institution. Therefore, we argue that before this practice is 
instituted, both the analgesic effect as well as the risk of postoperative hemorrhage associated 
with this dosing need to be further characterized. 
 
The decision to recommend QID dosing of analgesics for 9 days was chosen based upon 
previous studies which indicate that postoperative pain after extracapsular tonsillectomy using 
electrocautery persists above 2 on the faces pain scale-revised (range 0-6) through POD7 (19). 
Additionally, studies of postoperative bleeding indicate that the highest risk of incidence of 
 
8 
Last Updated: 26-Apr-2011 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
postoperative bleeding occurs on postoperative day 8 (20). Therefore, in order to assess the rate 
of bleeding associated with ibuprofen use, it seems reasonable to administer the drug throughout 
the period associated with greatest risk. 
 
A postoperative recommendation form will be placed on each chart for review by the nurses in 
the recovery rom and on the floor (if inpatient status). This form will state that no additional 
acetaminophen be administered to the participant, and instructing that analgesia be administered 
from study supplied medication or supplemental narcotics if indicated for breakthrough pain at 
the discretion of participating surgeons. It will also have standard anti-emetic medications listed. 
 
Pain control data will be collected using a standardized, validated questionnaires as well as 
additional questions regarding postoperative pain control and return to normal diet and sleep 
patterns (see attachment at end of proposal). These questionnaires have been used in previous 
studies evaluating ibuprofen and post-tonsillectomy pain (11, 12). Questionnaires for each 
postoperative day, as well as a 9 day supply of medication, will be dispensed at discharge. 
Patient’s caregivers will be asked to complete the questionnaire on a daily basis for the first eight 
postoperative days, and bring it, as well as any remaining medication, to the postoperative visit 
for review. Remaining syringes will be assessed to determine the total number of doses of 
medication each patient received over the 8 day postoperative period. 
 
All participating children and their parents will be advised to see medical evaluation emergently 
should a bleeding event occur, as is currently standard practice after adenotonsillectomy. All 
children with evidence of a bleed, such as a history of bleeding, active bleeding, or an 
oropharyngeal clot will be admitted, at least, for observation, at the discretion of participating 
surgeons. A large bore IV will be placed and IV fluids administered. Children with active 
bleeding or a large oropharyngeal clot will return to the operating room, at the discretion of the 
participating clinician, for control of hemorrhage under general anesthesia and endotracheal 
intubation. They will be instructed to discontinue the study drug, and take acetaminophen 
15mg/kg (maximum dose 650mg) every 4-6 hours for pain control. Children prescribed 
oxycodone for pain control postoperatively will be able to continue narcotics as well. 
 
At the end of the 14 day postoperative period, a study physician or participating research nurse 
will contact patients’ parents/guardians to question about postoperative bleeding events. In cases 
where bleeding occurred, the written and electronic hospital events will be evaluated for further 
information. Bleeding events will be classified according to the type of intervention taken. 
 
 
 
Response: 
Pain control questionnaires for each postoperative day, as well as a 9 day 
supply of medication (36 doses) will be dispensed at discharge. Patient’s caregivers will be 
asked to complete the questionnaire daily on the day of surgery and for the first eight 
postoperative days and bring it, as well as any remaining study medication, to the postoperative 
9 
Last Updated: 26-Apr-2011 
6. List study endpoints: How will the approach described give you the answer(s) to the 
questions you are investigating? 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
visit for review. Remaining medication will be measured to assess the total number of doses of 
medication that the patient received during the study period. 
 
All patients will be instructed to go to the emergency room if there is any evidence of a post- 
operative bleed for evaluation and treatment. Data collection will be performed by participating 
surgeons and the research nurse. He/she will contact the parents of patients at the end of the 14- 
day postoperative period. If an episode of bleeding occurs, the caller will review any pertinent 
emergency room, outpatient, inpatient and operating room records for further information 
regarding the nature of the bleed and required treatment. Admission for observation and/or 
return to the operating room for hemorrhage control will be recorded. 
 
Postoperative hemorrhage will be defined as any history of bleeding, mild or severe, occurring in 
the 14-day postoperative period.  Postoperative hemorrhage will be defined as primary 
(occurring <24 hours after surgery) and secondary (occurring >/= 24 hours after surgery). For 
each category, postoperative hemorrhage will be stratified into three levels of severity: 
• Level 1: children with any history of postoperative bleeding whether or not there was 
clinical evidence of bleeding. This level includes all children with a history of 
postoperative bleeding who were evaluated and/or treated by a physician in the 
emergency room, inpatient unit or operating room. 
• Level 2: represents all children who required inpatient admission for postoperative 
hemorrhage regardless of the need for operative intervention. This level of severity 
excludes children evaluated in the emergency room for reported postoperative 
hemorrhage who had no clinical evidence of hemorrhage or clot and were deemed 
safe for discharge. 
• Level 3: children who required admission and return to the operating room for control 
of post-tonsillectomy hemorrhage. 
 
 
 
 
 
Response: 
Patients with a known personal or family history of a bleeding disorder will 
be excluded. Patients with a history of asthma, kidney or liver problems will also be excluded. 
Patients with tonsillectomy or adenoidectomy performed using a cold knife technique, 
microdebrider, coblation or plasma knife. Patients on NSAIDs for other medical conditions, or 
 
10 
Last Updated: 26-Apr-2011 
7. Inclusion Criteria: List all inclusion criteria. Clearly describe how eligibility will be 
determined and by whom. 
by electrocautery alone for sleep disordered breathing or infectious tonsillitis will be included. 
Patients with complex medical conditions and craniofacial abnormalities will be included. 
Informed consent and child assent will be required for enrollment. 
Patients ages 2-18 undergoing tonsillectomy with or without adenoidectomy 
Response: 
8. Exclusion Criteria: List all exclusion criteria. Clearly describe how ineligibility will be 
determined and by whom. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
those who have taken NSAIDs within 1 week of surgery will be excluded. 
Patients with allergy 
to aspirin or other NSAIDs, acetaminophen, Red Dye #40 or Red Dye #33 will also be excluded. 
Pregnancy testing using urine beta-HCG will be performed on all children > 13 years of age, or 
those younger than 13 who are menstruating; this is the testing protocol used at the Children’s 
Hospital of Boston. Patients found to be pregnant will be excluded from participation. 
 
 
 
 
 
 
 
 
 
Response: 
In Dr. Gallagher and Dr. Hartnick’s study of the use of dexamethasone and the 
risk of postoperative bleeding (in press), 137 children received dexamethasone and postoperative 
tylenol, and there were three type 3 bleeds requiring return to the operating room for control of 
hemorrhage, giving a roughly 2% type 3 bleed rate. This is consistent with MEEI quality and 
outcomes data for 2005-2009, which demonstrated that 2.25% (SD 0.5) of tonsillectomies 
performed during the period required return to the OR (type 3 bleeding) for control of 
hemorrhage. Therefore, we calculated the sample size for the non-inferiority trial using a type 3 
11 
Last Updated: 26-Apr-2011 
9. Study Population: Specify characteristics of the study population (gender, age range, health 
status). State the target enrollment for a multi site trial here and describe any site specific 
restrictions, e.g. “Enrollment at MEEI will be limited to an age range of 18-45 although the 
sponsor’s protocol allows an age range of 5-45.” 
tonsillectomy with or without adenoidectomy by electrocautery alone for sleep disordered 
breathing or infectious tonsillitis. The total target enrollment for all participating study sites is 
722 (366 patients per arm). 
Males and females between the ages of 2 and 18 years undergoing 
Response: 
A. How many potential subjects do you have access to for this protocol? Specify the 
anticipated screening sample size at MEEI and the probable duration of this study. 
contributing attending was 200. The anticipated screen sample size at MEEI is 600 annually, 
and that roughly 200 participants will sign-up to participate per year. We project that each 
participating institution will contribute 200 study subjects per year, and that it will take 
approximately 2 years to reach our target enrollment of 722. We plan to apply for Continuing 
Review until we reach target enrollment, should this taken longer than 2 years. 
Over the last 2 years, the average number of tonsillectomies for each 
Response: 
B. How many subjects would you need to recruit at MEEI to meet your target enrollment 
within the indicated time period for this study? 
Response: 400 
C. Provide statistical justification of sample size. Include a statement about the statistical 
power of the study to test the major hypothesis. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
bleed rate of 2% as our predicted type 3 bleed rate for patients in the control (acetaminophen) 
arm. Our margin of inferiority was 3% between control and experimental groups. We then 
calculated our sample size into account taking into account a desire to perform 3 looks at the data 
(at approximately 10%, 50% and 100% enrollment) and a projected 5% loss to follow-up rate. 
 
We then calculated a projected sample size using a group sequential two proportions non- 
inferiority method using East v 5.4.2 and O’Brien-Flemming stopping boundaries determined by 
means of the Lan-DeMets approach with the following parameters: an alpha of 0.025, power of 
80%, 5% projected loss to follow up rate, control bleed rate of 2%, non-inferiority margin of 3%, 
and 3 anticipated looks at the data. We calculated our total enrollment will need to be 722 
subjects (366 per arm), with interval looks at n= 102 and n= 362 patients. 
 
 
 
 
Response: 
We plan to initially analyze the crude association between ibuprofen and 
bleeding rate using simple, univariate analysis. We will then construct a multivariate logistic 
regression model including ibuprofen exposure, pain control, outcome, and potential 
confounding factors such as age, surgical indication, gender, and operating surgeon. Analysis 
will be performed using an intention to treat analysis. Impact of losses to follow-up will be 
assessed using sensitivity analysis. Statistical analysis and data management will be performed 
using STATA, SAS and Microsoft Excel. 
 
1. At the enrollment of 102, 362 and 722 participants, the study will be unblinded and data 
reviewed using both univariate and multivariate analysis. 
a. A simple, uni-variate analysis will be performed to evaluate the association 
between ibuprofen and bleeding (we are primarily interested in evaluating the 
association between ibuprofen and type 3 bleeding). 
i. The null hypothesis (ibuprofen does not increase the risk of type 3 
postoperative hemorrhage) will be rejected if there is a greater than 3% 
increase, which is the preset equivalence margin, in type 3 bleeding in the 
ibuprofen cohort in comparison to the acetaminophen cohort. 
1. Based on statistical analysis, P values will be significant in the 
following conditions: 
a.   1st look (n=102) if p < 0.00001 
b. 2nd look (n=362) if p < 0.001525 
c. Final look (n= 722, total enrollment) if p<0.025 
b. A multi-variate logistic regression model will be used to evaluate ibuprofen 
exposure, pain control, outcome and potential confounding factors such as 
narcotics use, age, surgical indication, gender, and operating surgeon. 
 
 
 
12 
Last Updated: 26-Apr-2011 
D. Describe how data collected will be analyzed. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
1. Postoperative analgesia: For the first 8 postoperative days, children will be administered 
QID, weight based analgesia from medication provided by the inpatient pharmacy at MEEI. 
Medication will be administered from an amber colored bottle containing 36 dosages of 
weight based medication. Each bottle will specify the patient’s name, medical record 
number, and instructions regarding the volume of medication to be measured and 
dispensed for each dosage. The volume of medication dispensed for each child will be 
manipulated with OraBlend solution such that the weight based dose of ibuprofen volume 
will equal the weight based dose of acetaminophen volume; both medications will be dosed 
QID. Surgeons, nursing staff, and patients and their families will be blinded regarding the 
type of medication administered (acetaminophen vs. ibuprofen). Acetaminophen will be 
given as 15mg/kg dosing (maximum dose 650mg) and ibuprofen will be given as 10mg/kg 
dosing (maximum dose 600mg). Children with breakthrough pain eligible for narcotics 
(based upon age, OSA status) will be given prescriptions for weight based doses of 
oxycodone 1mg/1mL elixir (0.05-0.1mg/kg every 4-6 hours) as well as prescribed this 
medication for breakthrough pain while inpatients. After 9 days, patients will be instructed 
to take acetaminophen 15mg/kg (max dose 650mg) every 4-6 hours as needed for 
breakthrough pain. They will be instructed not to use nonsteroidal anti-inflammatory 
drugs (NSAIDS) in the postoperative period (14 days). 
 
2. Surveys: On the postoperative day and during the first 8 postoperative days, parents will 
be asked to complete a questionnaire about their child’s pain control on a daily basis. The 
questionnaire used includes a validated questionnaire about postoperative pain control, as 
well as additional questions regarding postoperative pain control and return to normal diet 
and sleep patterns. These questionnaires have been used by previous studies evaluating 
the use if ibuprofen for post-tonsillectomy pain control. Parents will be asked to being this 
questionnaire to their postoperative visit for data collection and review. 
 
3. Collection of post-operative hemorrhage data: All patients will be instructed to go to the 
emergency room if there is any evidence of a post-operative bleed for evaluation and treatment. 
Data collection will be performed by participating surgeons and the research nurse. He/she will 
contact the parents of patients at the end of the 14-day postoperative period. If an episode of 
bleeding occurs, the caller will review any pertinent emergency room, outpatient, inpatient and 
operating room records for further information regarding the nature of the bleed and required 
treatment. Admission for observation and/or return to the operating room for hemorrhage 
control will be recorded. 
 
Postoperative hemorrhage will be defined as any history of bleeding, mild or severe, occurring in 
the 14-day postoperative period.  Postoperative hemorrhage will be defined as primary 
(occurring <24 hours after surgery) and secondary (occurring >/= 24 hours after surgery). For 
each category, postoperative hemorrhage will be stratified into three levels of severity: 
 
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Last Updated: 26-Apr-2011 
10. Study Specific Procedures: Clearly list all procedures (interventions, tests, surveys, etc.) to 
be performed for research purposes. 
Response: 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
• Level 1: children with any history of postoperative bleeding whether or not there was 
clinical evidence of bleeding. This level includes all children with a history of 
postoperative bleeding who were evaluated and/or treated by a physician in the 
emergency room, inpatient unit or operating room. 
• Level 2: represents all children who required inpatient admission for postoperative 
hemorrhage regardless of the need for operative intervention. This level of severity 
excludes children evaluated in the emergency room for reported postoperative 
hemorrhage who had no clinical evidence of hemorrhage or clot and were deemed 
safe for discharge. 
• Level 3: children who required admission and return to the operating room for control 
of post-tonsillectomy hemorrhage. 
 
 
 
Response:  All females of child bearing potential shall undergo a pregnancy test prior to 
surgery, regardless of their participation in the study as part of standard clinic care at MEEI. All 
patients will be administered 15mg/kg (max dose 650mg) of acetaminophen preoperatively prior 
to arrival in the preoperative area and dexamethasone 0.5mg/kg IV (maximum dose of 8mg) or 
methylprednisolone (SoluMedrol) 2.5mg/kg IV (maximum dose of 40mg) in the operating room 
prior to surgical commencement, which is standard practice at MEEI. The standard method of 
tonsillectomy among participating surgeons will be extracapsular monopolar electrocautery with 
standard settings of 12 watts (fulgurate) using a spatula tip. Bleeding will be controlled with 
suction cautery on a setting of 12-18 watts (fulgurate). Adenoidectomy will be performed at 30 
watts (fulgurate). Anesthetic technique, perioperative analgesia with narcotics, and post- 
operative care will remain equivalent between the two study arms. Antibiotics will not be 
administered in the perioperative period. Postoperative anti-emetic therapy will be standardized 
by all collaborating physicians using standardized order sets. All patients will be prescribed 
postoperative analgesia, and those eligible to receive narcotics will also be prescribed oxycodone 
elixir. Postoperative hemorrhage will be managed the same, regardless of study participation. 
 
 
 
 
 
 
 
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Last Updated: 26-Apr-2011 
11. Standard of Care Procedures: Clearly list all standard of care (standard therapy) 
procedures (interventions, tests, etc.) to be performed regardless of the subject’s enrollment in 
the study, but that will be included in the research assessment. 
12. Alternatives: For studies offering treatment, what treatment alternatives are available 
outside of this research? 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
Response: 
None. Patients unwilling to enroll in the study will have the tonsillectomy with 
or without adenoidectomy performed and receive postoperative analgesia of acetaminophen with 
or without supplemental narcotic medication according to current practice standards. 
 
 
 
Response: ach subject will require 3 visits. An initial visit/consultation/preop, the day of 
surgery, and a post-operative visit 2-4 weeks after surgery. The initial visit would last 
approximately 45 minutes. The surgery, including anesthesia recovery time, would last 
approximately six hours, and the postoperative visit would be about 15 minutes in duration. This 
time commitment does not deviate from the commitment required for patients undergoing 
tonsillectomy who will not be participating in the study. 
 
 
 
 
 
 
 
 
15 
Last Updated: 26-Apr-2011 
13. Describe the Time Commitment for Each Subject, e.g. 2 hours per visit/5 visits/10 hours 
total. For complex studies, be specific for each portion of the study. 
We approximate study participation will require a roughly 2 hour time commitment for each 
subject in addition to the time described above. This incorporates a 10 minute time commitment 
per day to complete study-related questionnaires regarding postoperative pain control, as well as 
15 minutes for questionning about postoperative bleeding during both a phone survey at the end 
of a 14 day postoperative period, and 15 minutes at the time of the scheduled postoperative visit. 
14. Cost of Participation: Clearly describe any costs to Subjects as part of this research, e.g. 
copay for standard of care procedures, parking, etc. 
Response: 
Patients will be responsible for any fees associated with the scheduled procedure 
(i.e. co-pays, deductibles, etc.) as determined by their insurance. 
15. Payments for Participation: Describe all payments and/or reimbursement subjects will 
receive during the study, e.g. travel reimbursement, stipend, etc. Include mechanism for 
payment, e.g. cash, check, gift, etc. 
Response: 
Patients will not be paid or reimbursed for participation in this study. 
16. Subject Safety:  Describe explicitly the methods and procedures for ensuring subjects’ 
safety. Provide objective criteria for removing a subject from the study, e.g. objective criteria for 
worsening disease/lack of improvement, and/or unacceptable adverse events. The inclusion of 
objective drop criteria is especially important in studies designed with placebo control groups. 
Response: 
We propose to establish a data and safety monitoring board (DSMB). The 
board will receive notification each time a bleeding event occurs in a study patient. Bleed rate 
data will be examined on a bi-annual basis (every 6 months), or if the objective, type 3 bleed rate 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
All participating children and their parents will be advised to see medical evaluation emergently 
should a bleeding event occur, as is currently standard practice after adenotonsillectomy. All 
children with evidence of a bleed, such as a history of bleeding, active bleeding, or an 
oropharyngeal clot will be admitted, at least, for observation. A large bore IV will be placed and 
IV fluids administered. Children with active bleeding or a large oropharyngeal clot will return to 
the operating room, at the discretion of the participating clinician, for control of hemorrhage 
under general anesthesia and endotracheal intubation. They will be instructed to discontinue the 
study drug, and take acetaminophen 15mg/kg (maximum dose 650mg) every 4-6 hours for pain 
control. Children prescribed oxycodone for pain control postoperatively will be able to continue 
narcotics as well. 
 
 
EXPECTED RISKS AND DISCOMFORTS 
 
 
 
16 
Last Updated: 26-Apr-2011 
exceeds 6% (three times the expected rate of 2% type 3 bleeding based on a review of the 
literature and MEEI quality and outcomes data) after enrollment of the first 100 subjects. The 
study will be terminated if the type 3 bleed rate in either arm exceeds greater than 6%. 
Interim 
data-analyses will also be performed after recruitment of 102 subjects, and after 50% recruitment 
(n=362). At the first look, if the type 3 hemorrhage rate for the ibuprofen cohort exceeds 3% 
above the tylenol group, which is the non-inferiority interval used for our statistical design, with 
p<0.00001, the study will be terminated. The study will be terminated at this point if the type 3 
bleed rate exceeds 6% (7 type 3 bleeding events). At the second look (n=362), the study will be 
terminated if the type 3 hemorrhage rate for the ibuprofen group exceeds 3% above the tylenol 
group, with p<0.001525. The study will also be terminated at this point if over 22 type 3 
bleeding events have occurred (>6% objective bleeding rate). 
17. Subject Injury: Describe the medical treatment available if injury occurs. Where and from 
whom will treatment be obtained? Are there limits to the treatment available? Who will pay for 
this treatment? Will the subject be responsible for any costs for treatment, e.g. co-pay? 
Collaborators should a participant be injured as the result of participating in this study. Third 
party payers will be billed for any emergency services, when applicable and the participant will 
be responsible for any deductibles and co-payments required by the third party payer. There will 
be no compensation as the result of any injury. 
Emergency treatment will be provided by Dr. Hartnick and the Co- 
Response: 
18. Describe any foreseeable risks and discomforts to subjects: Include those related to 
drugs/devices/procedures being studied and/or administered/performed solely for research 
purposes. Include psychosocial risks and risks related to privacy and confidentiality. Describe 
risks to developing fetus or nursing infant if applicable. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
Response: Risks to subjects will be minimized through the use of standardized operative 
procedure. All subjects will receive postoperative analgesia, either tylenol or ibuprofen, both of 
which have been proven effective analgesics after tonsillectomy. All subjects will be educated 
regarding signs and symptoms of postoperative hemorrhage and advised to seek emergency care 
should bleeding occur; this is also standard practice. 
 
 
EXPECTED BENEFITS 
 
 
17 
Last Updated: 26-Apr-2011 
Response: Tonsillectomy with or without adenoidectomy is not without risk. The following are 
potential risks of surgery that apply to both arms of the study: pain, postoperative hemorrhage, 
anesthetic and airway risks, aspiration, post-obstructive pulmonary edema, atlanto-axial 
subluxation, mandible fracture and dislocation, eustacian tube injury, injury to the lips, teeth, 
tongue and gums, dehydration, nasopharyngeal stenosis, and velopharyngeal insufficiency. 
19. Describe how the risks to subjects will be minimized, i.e. using procedures consistent 
with sound research design and which do not unnecessarily expose subjects to risk or, whenever 
appropriate, by using procedures already being performed on the subjects for diagnostic or 
treatment purposes. 
Data will be stored on a Microsoft Excel database which will be kept on a password protected 
server that the principal and associate investigators and research nurse can access to enter their 
data. No data will be stored with an associated patient name. Code sheets that link the subject 
number to patient name will be kept in a locked file on only one computer with a backup copy of 
the file stored in a locked cabinet in the principal investigator’s office. The code sheets will be 
maintained by the principal and associate investigators, and the computer used to store the code 
will be different than that used to store the Excel database. Only study investigators will have 
access to the passwords. No data linked to a subject will be released without written permission 
from the subject. 
20. Describe both the expected benefits to individual subjects participating in the research 
and the importance of the knowledge that may reasonably be expected to result from the study. 
Provide a brief, realistic summary of potential benefits to subjects, e.g. “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.” 
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, i.e. through increased knowledge of human physiology and behavior, 
improved safety or technological advances, etc. 
Response: Tonsillectomy is the second most common surgery performed in the pediatric 
population. Knowledge gained by this trial will help to improve the safety of tonsillectomy, and 
potentially pain management after surgery, for hundreds of thousands of children each year. 
While meta-analysis of NSAID use after tonsillectomy has suggested NSAID use may not 
increase the risk of bleeding, further research is needed to evaluate specific NSAIDs and the 
timing of administration. Therefore, it is surprising that the American Academy of 
Otolaryngology would advocate the use of ibuprofen in the perioperative period when further 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
RECRUITMENT METHODS 
 
 
EQUITABLE SUBJECT SELECTION 
 
 
 
 
18 
Last Updated: 26-Apr-2011 
research is warranted. In Europe, administration of ibuprofen and other NSAIDs after 
tonsillectomy in the pediatric population is widely accepted, though members of the American 
otolaryngology community are more hesitant to use them due to the theoretical increased risk for 
bleeding. The results of this study would help to specifically address concerns regarding the use 
of ibuprofen in the postoperative period. The results of such a definitive study would possibly 
affect our standards of care, as well as both national and international norms. 
21. Describe a) when, b) where, and c) how potential subjects will be recruited, methods 
that will be used to identify potential subjects, and materials that will be used to recruit subjects, 
i.e. posters, phone scripts, letters, etc. Attach copies of posters, scripts, letters, etc., to be used 
for recruitment purposes to this application package. 
his Co-Collaborators. Participants will be identified when they are scheduled for a tonsillectomy 
and approached to participate in this study. No other recruitment materials will be used. 
Participants will be recruited from the medical practices of Dr. Hartnick and 
Response: 
22. The risks and benefits of the research must be fairly distributed among the populations that 
stand to benefit from it. No group of persons, i.e. men, women, pregnant women, children and 
minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so. Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research. 
patients already scheduled for tonsillectoy and therefore all have an equal chance of participating 
in this study. Subjects meeting any exclusion criteria will not be included. 
All subjects who meet inclusion criteria will be recruited by the P.I. from 
Response: 
23. Provide justification for involving vulnerable subjects and fill out the relevant 
supplemental form. 
[]Adults unable to consent (fill out supplemental form IX) 
[X] Individuals who are not yet adults (infants, children, teenagers) (fill out supplemental form 
XII) 
[X] Pregnant women/females of childbearing potential (fill out supplemental form XI) 
[] Prisoners (check with our office for specific form) 
[] Employees, study staff, students, residents, fellows (describe safeguards provisions) 
[X] Non-English Speaking (answer questions 24 & 28) 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
INFORMED CONSENT PROCESS 
 
 
 
 
 
Response: 
Participation in the study will be introduced prior to surgery to both patent 
and child. Consent and assent (for eligible age appropriate children and if necessary per clinical 
site) will be signed prior to the surgery. 
 
 
 
 
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Last Updated: 26-Apr-2011 
24. If non-English speaking subjects are to be excluded from participation in the research, 
please provide a scientific rationale for doing so. Individuals who do not speak English should 
not be denied participation in research solely due to language. 
Response: 
NA 
25. Explain in detail a) how, b) when, c) where, and d) by whom consent is obtained. 
Describe the timing of consent, i.e. how long subjects will be given to consider participation. 
For most studies involving more than minimal risk and all studies involving investigational 
drugs/devices, a licensed physician investigator must obtain informed consent. 
tonsillectomy is scheduled. The Principal Investigator of each participating site will introduce the 
study and answer any questions patients and their families may have. They will be given the 
opportunity to consider participation until prior to arrival in the preoperative area. Those who do 
not sign an ICF will not be included in the study. 
The study will be introduced to the patients and his or her family at time the 
Response: 
26. When subjects are to be enrolled from among the investigators’ own patients or MEEI 
employees describe how potential for coercion will be avoided. 
tonsillectomy. They will be informed that non-participation in the study will not affect the 
surgery already schedule. Thus, there will be no potential for coercion. 
All enrolled subjects will be patients who are already scheduled for a 
Response: 
27. For research involving minors, please explain how parental permission and child assent 
will be obtained. 
28. For research involving non-English speaking subjects, specify potential languages and 
explain how consent will be obtained (e.g. use of MEEI Interpreter Services and/or translated 
consent forms). 
Services will be utilized. 
For subjects involving non-English speaking subjects, MEEI Interpreter 
Response: 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
DATA/SAFETY MONITORING PLAN 
 
 
 
 
20 
Last Updated: 26-Apr-2011 
29. Describe plan to periodically evaluate the data collected regarding both harms and 
benefits to determine whether subjects remain safe. This plan should include a description of 
the safety and/or efficacy data that will be reviewed, the planned frequency of review, and who 
will be responsible for this review and for determining whether the research should be altered or 
stopped. Describe any stopping rules for the study, when appropriate. Depending upon the risk 
level, size and complexity of the study, the investigator, an expert group, an independent Data 
and Safety Monitoring Board (DSMB) or others might be assigned primary responsibility for this 
monitoring activity. 
Note: Regardless of data and safety monitoring plans by the sponsor or others, the 
Principal Investigator is ultimately responsible for protecting the rights, safety, and 
welfare of subjects under his/her care. 
Response: We propose to establish a data and safety monitoring board (DSMB). The board will 
receive notification each time a bleeding event occurs in a study patient. Bleed rate data will be 
examined on a bi-annual basis (every 6 months), or if the objective, type 3 bleed rate exceeds 
9.3% (1 SD above the mean bleed rate for tonsillectomy) after enrollment of the first 100 
patients at MEEI. The study will be terminated if the type 3 bleed rate in either arm exceeds 
greater than 6%. Interim data-analyses will also be performed after recruitment of 102 subjects, 
and after 50% recruitment (n=362). At the first look, if the type 3 hemorrhage rate for the 
ibuprofen cohort exceeds 3% above the tylenol group, which is the non-inferiority interval used 
for our statistical design, with p<0.00001, the study will be terminated. The study will be 
terminated at this point if the type 3 bleed rate exceeds 6% (7 type 3 bleeding events). At the 
second look (n=362), the study will be terminated if the type 3 hemorrhage rate for the ibuprofen 
group exceeds 3% above the tylenol group, with p<0.001525. The study will also be terminated 
at this point if over 22 type 3 bleeding events have occurred (>6% objective bleeding rate). Dr. 
Stacey Gray, Dr. Maynard Hansen and Dr. Mark Volk have been recruited to serve as the DSMB 
for this study. 
30. Describe the plan to be followed by the Principal Investigator/study staff for review of 
adverse events experienced by subjects under his/her care, and when applicable, for review of 
sponsor safety reports and DSMB reports. 
Response: At the end of a 14-day postoperative period, all subjects will be interviewed 
regarding any bleeding events. In the case of bleeding, review of the electronic record will be 
performed to further investigate the severity of bleeding and the interventions taken to control 
hemorrhage. The DSMB will be notified each time a bleeding event occurs in a study patient. 
Bleed rate data will be examined on a bi-annual basis (every 6 months), or if the objective, type 3 
bleed rate exceeds 6% (three times the mean type 3 bleed rate for tonsillectomy based on review 
of the literature and MEEI quality and outcomes data) after enrollment of the first 100 patients at 
MEEI. The study will be terminated if the type 3 bleed rate in either arm exceeds greater than 
6%. Interim data-analyses will also be performed after recruitment of 102 subjects, and after 
50% recruitment (n=362). At the first look, if the type 3 hemorrhage rate for the ibuprofen cohort 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
 
QUALITY ASSURANCE 
 
 
 
 
 
 
21 
Last Updated: 26-Apr-2011 
exceeds 3% above the tylenol group, which is the non-inferiority interval used for our statistical 
design, with p<0.00001, the study will be terminated. The study will be terminated at this point 
if the type 3 bleed rate exceeds 6% (7 type 3 bleeding events). At the second look (n=362), the 
study will be terminated if the type 3 hemorrhage rate for the ibuprofen group exceeds 3% above 
the tylenol group, with p<0.001525. The study will also be terminated at this point if over 22 
type 3 bleeding events have occurred (>6% objective bleeding rate). 
31. When the Principal Investigator is also the regulatory sponsor of the IND/IDE, include the 
plan for identifying, reviewing and, when applicable, sharing adverse events with investigators at 
other sites. Specify the time frame. 
Note: In addition to the adverse event reporting requirements to the sponsor of FDA, the 
principal investigator must follow the Human Studies Committee Policy for Reporting 
Adverse Events and Unanticipated Problems. 
Response: 
NA 
32. Describe your process to ensure that all persons assisting with the trial are sufficiently 
knowledgeable about the protocol, the investigational product(s), and their trial-related duties 
and functions. Please do not include CITI training, as this is a requirement for doing human 
subjects research and is not specific to your protocol. 
Response: All study personnel will be required to be familiar with the study protocol and 
previous research involving nonsteroidal anti-inflammatory use after tonsillectomy. A procedure 
manual, outlining subject recruitment, consent and assent procedures, postoperative 
management, data aquisition and recording will be drafted, an all study participants will be 
required to be familiar with and follow these procedures. 
33. Describe the plan to be followed by the Principal Investigator/study staff to monitor the 
validity and integrity of the data and adherence to the IRB-approved protocol. 
data at the site on a semi-annual basis to ensure accuracy and adherence to study protocol. 
Should he find any discrepancy in the data, he will review the study protocol with all study staff 
involved, and retrain and remediate as necessary. 
The principal investigators at each participating site will review all current 
Response: 
34. Specify who will be responsible for monitoring and the planned frequency of monitoring, 
i.e. who will review the accuracy and completeness of case report form entries, source 
documents and informed consent. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
CONFIDENTIALITY 
35. Check all patient identifiers collected for this study that will be recorded with or linked 
by code to the data. If any categories are checked, you will need to obtain HIPAA authorization 
from the subject or a waiver of HIPAA authorization from the HSC to perform research. 
 
[]None of the listed identifiers will be recorded as part of the study 
[X] Name 
[] Telephone Number 
[] Social Security Number 
[] Fax Number 
[X] Medical Record Number 
[] Email Address 
[]Address by Street Location []Web URL’s 
[]Address by Town/City/Zip Code 
[]Internet Protocol (IP) Address 
[]Health Plan Beneficiary Number 
[]Account Number 
[]Certificate/License Number []Ages Over 89 
[]Full Face Photographic Image 
X[]Elements of Dates (Admission/Discharge Date, Procedure Date, Date of Birth or Death) 
[]Vehicle ID Number and Serial Number Including License Plate Number 
[]Medical Device Identifiers and Serial Number 
[]Biometric Identifiers (e.g. fingers or voice prints) 
[]Other unique identifiers or code that can be used to identify the participant 
 
 
 
 
 
 
 
22 
Last Updated: 26-Apr-2011 
Response: The Principal Investigators at each participating site will be responsible for 
monitoring and the planned frequency of monitoring the data. 
36. If you selected “Other” please explain: 
Response: 
37. Describe the methods used to protect the privacy of subjects and maintain confidentiality 
of data collected. This typically includes such practices as substituting codes for names and/or 
medical record numbers, removing face sheets or other identifiers from completed surveys 
and/or questionnaires, proper disposal of printed computer data, limited access to study data, use 
of password-protected computer databases, training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 
Last Updated: 26-Apr-2011 
Note: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of 
sensitive data, such as genetic, sexual, or criminal. 
back up and more protection against data breach. Access will be limited to authorized study staff 
through password protection. Published data will not have any personal identification attached. 
Study-related PHI will be maintained on a shared server (T drive) to allow for 
Response: 
38. How long will data be retained, i.e. when and how link to identifiable data be 
destroyed? 
drive). Once the study has completed, all identifiable data that was collected will be kept 
according to MEEI guidelines or de-identified according to HSC recommendations. 
As mentioned above any study-related PHI will be kept on shared server (T 
Response: 
39. For specimens or data being sent to other institutions, please indicate to whom the 
specimens or data will be sent, and what specific identifiers (per question 35) will be sent. 
Response: NA 
40. Will specimens/data be stored at outside sites for future use not described in the 
protocol? Will subjects be able to withdraw their specimens/data and, if so, how would they do 
so? When appropriate, submit documentation of IRB approval from the recipient institution. 
Response: 
NA 
41. When specimens or data collected by researchers outside MEEI will be sent to MEEI 
investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used to link the specimens/data to individual 
subjects. When appropriate, submit documentation of IRB approval and a copy of the IRB- 
approved consent form from the institution where the specimens/data were collected. 
Response: Data collected from other participating institutions will be entered into excel files in a 
deidentified fashion before they are shared with the investigators at MEEI. Other participating 
institutions will also require their own IRB approval, DSMB, and all questionnaire and 
consent/assent forms will also be approved by those institutions. 


Human Studies Committee 
Tel: 617-573-6939 
Email: HSC@meei.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Last Updated: 26-Apr-2011 
42. Provide any additional information you feel is important for the Committee to know about 
your project. 
Response: 
43. INVESTIGATOR- INITIATED STUDIES 
This section should be completed by the PI for investigator-initiated projects that have not 
been peer-reviewed by sponsoring agencies. The checklist below is designed to assist the PI 
in developing a project that meets peer-review standards of scientific design, including 
appropriate scientific rationale, study endpoints, biostatistical justification, and 
recruitment goals. 
Please check the boxes below to indicate these topics have been covered in detail in this 
application. 
[X]Preliminary data from the literature (or from your own previous studies) 
[X]Specific aims and corresponding hypotheses 
[X]How the question or hypothesis being tested will contribute important knowledge to the 
field 
X[]The primary outcome (and secondary outcomes as appropriate) 
[X]Justification that the study design is appropriate for answering the study hypothesis 
[X]Justification that the study is powered and controlled (sample size, appropriate control 
(s), adequate plan for statistical analysis) for this purpose 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
 
 
 
 
COVER PAGE 
 
 
Clinical Protocol Title: Postoperative Ibuprofen and the Risk of Bleeding After Tonsillectomy with or 
without Adenoidectomy 
 
HSC #: 11-054H 
IRBNet ID: 242942 
Clinical trials.gov number: NCT01605903 
 
Version 6 6/01/16 
Phase of clinical investigation: Phase 1 
 
Sites of Investigation: 
Massachusetts Eye and Ear Infirmary; Boston, MA 
Madigan Army Base; Tacoma, WA 
Naval Medical Center of San Diego, Department of Otolaryngology; San Diego, CA 
Naval Medical Center, Department of Otolaryngology, Portsmouth, VA 
Brooke Army Medical Center, San Antonio, TX 
 
IND/IDE number: NA 
Investigational drug(s) or device(s): NA 
 
Regulatory Sponsor: 
Christopher Hartnick, MD 
Department of Otolargyngology 
Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114 
Funding Sponsor: Intradepartmental funding at MEEI, US Army and Navy at other sites. 
 
Study Monitor: 
Data Safety and Monitoring Board for MEEI Site: Dr. Stacey Gray (MEEI), Dr. Maynard Hansen 
(MEEI/NWH), Dr. Mark Volk (CHB) 
 
Medical Director: 
Christopher Hartnick, MD 
Department of Otolargynology 
Massachusetts Eye and Ear Infirmary 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
243 Charles Street 
Boston, MA 02478 
617-573-4206 
 
MEEI: 
Principal Investigator: Christopher Hartnick, MD 
CoInvestigators: Donald Keamy, MD; Michael Cohen, MD; Gillian Diercks, MD; Jennifer Setlur, MD; Jill 
Comins, NP; Sarah Bowe, MD 
Department of Otolaryngology 
Massachusetts Eye and Ear Infirmary 
243 Charles Street 
Boston, MA 02478 
617-573-4206 
 
Madigan Army Hospital 
Principal Investigator: Mark Boseley, MD, MS Epi 
CoInvestigator: Brian Chen, MD, CPT, MC; Derek Rogers, MD 
Department of Otolaryngology 
Madigan Army Medical Center 
Madigan Army Medical Center 
BLDG 9040A Jackson Ave 
Tacoma, WA 98431-1100 
 
San Diego Naval Hospital 
Principal Investigator: LCDR Matthew Brigger, MD, MPH (ended 1/1/16); Philip Gaudreau, MD (started 
1/1/16) 
CoInvestigators: LT Colleen Perez, MD; Cheryl McNeal BS, CRC. 
Department of Otolaryngology 
Naval Medical Center 
3460 Bob Wilson Drive, Suite 200 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
San Diego, CA 92134-2200 
 
Portsmouth Naval Hospital 
Principal Investigator: Thomas Gallagher, DO 
Co-Investigator: Jonathan Melzer, MD 
Department of Otolaryngology 
Navy Medical Center, Portsmouth 
620 John Paul Jones Circle 
Portsmouth, VA 23708-2197 
757-953-2825 
 
Brooke Army Medical Center 
Principal Investigator: Stephen Maturo, MD 
Department of Otolaryngology 
Brooke Army Medical Center 
3851 Roger Brooke Drive 
San Antonio, TX 78219 
210-916-2504 
 
Clinical Laboratory(ies), Technical Department(s), and Institution(s) Providing Clinical Study Services: 
 
Massachusetts Eye and Ear Infirmary 
Clinical Pharmacist. Christine Finn, PharmD 
Massachusetts Eye and Ear Infirmary 
243 Charles Street 
Boston, MA 02478 
617-573-3315 
 
San Diego Naval Hospital 
Clinical Pharmacist. Mihaela Gruita, Pharm D 
Naval Medical Center 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
San Diego, CA 
619-532-8595 
Mihaela.Gruita@med.navy.mil 
 
Madigan Army Medical Center 
Clinical Pharmacist. Dennis Beaudoin, Pharm D 
Madigan Healthcare System 
Tacoma, WA 
253-968-1943 
dennis.r.beaudoin.civ@mail.mil 
 
Portsmouth Naval Medical Center 
Clinical Pharmacist. Richard (Tim) Gendron, PharmD 
Naval Medical Center 
Portsmouth, VA 
757-953-0252 
Richard.Gendron@med.navy.mil 
 
Brooke Army Medical Center 
Clinical Pharmacist. Irene Lo, RPh 
Brooke Army Medical Center 
San Antonio, TX 
210-916—252 
Irene.w.lo.civ@mail.mil 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
 
 
 
STUDY DESIGN SCHEMATIC 
 
 
RECRUITMENT 
MEEI: Drs. Hartnick, Keamy, Cohen, 
Setlur, Diercks (starting 9/1/16) 
Approximately 250 patients/year 
Drs. Boseley and Rogers (Madigan Army Base, Tacoma, WA) 
Drs. Brigger and Gaudreau (Naval Medical Center, San Deigo, CA) 
Dr. Gallagher (Naval Medical Center, Portsmouth, VA) 
Dr. Maturo (Brooke Army Medical Center, San Antonio, TX) 
Approximately 400 patients/year 
 
 
 
 
 
Patients ages 2-18 
 
Inclusion Criteria 
 
Exclusion Criteria 
Known personal/family h/o bleeding disorder 
Tonsillectomy with or without adenoidectomy 
for recurrent tonsillitis or SDB 
Performed by electrocautery alone 
 
 
 
 
INTERVENTION 
Receive acetaminphen 15mg/kg (max dose 
Asthma, kidney or liver problems 
Cold knife, microdebrider, plasma blade, coblation 
technique 
On NSAIDs for other conditions or if NSAIDs taking 
within 1 week of surgery 
Taking steroids 
Allergy to ASA, NSAIDs, acetaminophen, Red Dyes 
 
Ibuprofen 100mg/5mL 
650mg) preop 
Receive dexamethasone 0.5mg/kg (max 
dose 8mg) in OR 
No antibiotics administered 
Extracapsular tonsillectomy performed 
with electrocautery (12 watt), 
adenoidectomy performed with suction 
cautery (30 watt), hemostatis with suction 
cautery (12-18 watt) 
 
Randomized 
(Leader®); 10mg/kg (max dose 
600mg) po QID x 8 days to start 
4 hours after preop 
acetaminophen dose. 
+ 
Acetaminophen 160mg/5mL 
(Leader®); 15mg/kg (max 
dose 650mg) po QID x 8 days 
to start 4 hours after preop 
acetaminophen dose. 
9 daily postoperative pain 
questionnaires and 
medication dosing records. 
 
Oxycodone 1mg/1mL, 0.05- 
0.1mg/kg if elibile 
 
 
 
 
DATA ACQUISITION 
Bleeding Questionnaire performed at the 
postoperative visit 
Dosing/Pain Questionnaires , Left-over medication 
collected at the Postoperative Visit 
Bleed Categories 
Primary (within 24 hours) or Secondary 
+ 
Type 1: History of Postoperative Bleeding, No intervention. 
Type 2: History of Bleeding, Admitted for Observation. 
  
 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
 
SAFETY MONITORING 
 
DSMB notified each time there is a study patient bleed, 
total number of bleeds and total enrollment reported. 
 
 
 
After enrollment of 100 patients 
Examine Bleed Rate 
 
 
 
Objective, Type 3 Bleed Rate Exceeds 6%? 
 
 
 
No 
Continue recruitment, Reexamine bleed rate every 6 months. 
Yes 
Stop Study 
 
STATISTICAL ANALYSIS 
First Look: Unblind study at n=102. If 3% difference between groups for Type 3 bleeding with 
p<0.00001, or >7 type 3 bleeds (> 6% of study population), terminate Study. Otherwise continue. 
Second Look: Unblined study at n=362 (halfway point). If 3% difference between groups for Type 3 
bleeding with p<0.001525, or > 22 type 3 bleeds (>6% of study population), terminate Study. 
Otherwise continue. 
Final Look: Stop enrollment at n= 722 and unblind study. If 3% difference or more between study 
groups, p<0.025, the difference is significant. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
 
 
 
1. CLINICAL PROTOCOL 
 
 
1.1 Background 
Tonsillectomy with and without adenoidectomy is one of the most commonly performed 
surgical procedures in the pediatric population. The incidence of adenotonsillectomy has 
increased over the past four decades (1). This is mainly due to increased awareness of the 
potential adverse consequences that pediatric sleep disordered breathing (SDB) may have on 
development and long-term pulmonary and cardiovascular health.  SDB has surpassed 
recurrent tonsillitis as the most common indication for adenotonsillectomy in children (2-5). 
Over the past decade, according to the CDC’s National Health Statistic Report on ambulatory 
surgery performed in the US, annual rates of tonsillectomy performed with and without 
adenoidectomy in children aged 15 and younger increased from 287,000 to 530,000 (6, 7). 
Adenotonsillectomy is the second most common procedure performed on children under the 
age of 15. Although generally considered a safe procedure, adenotonsillectomy has significant 
morbidity and potential for complications, particularly in the pediatric population. 
Complications include postoperative hemorrhage, dehydration, pain, anesthetic complications 
and airway risks, aspiration, and post-obstructive pulmonary edema (8). In young children, the 
risk of adenotonsillectomy is more critical due to smaller airways and respiratory reserve, as 
well as smaller blood volume (5). 
Postoperative bleeding can be categorized as a primary event, occurring < 24 hours after 
surgery, or a secondary event, occurring >24 hours after tonsillectomy. Additionally, events can 
be further described by the interventions taken, such as emergency room visits, admission for 
observation, or return to the operating room to achieve hemostasis. Postoperative bleeding 
rates, including both primary and secondary events, range from 3.3-20%, with a mean of 4.5% 
(9). Thus, annually, tens of thousands of children experience exposure to potentially life- 
threatening postoperative hemorrhage, often requiring readmission, anesthetic exposure, and 
operative control of hemorrhage. 
Postoperative pain contributes significantly to post-tonsillectomy morbidity. While 
narcotics are effective in controlling postoperative pain, they are often contraindicated, 
particularly in children with sleep disordered breathing, because of their potentially adverse 
side effects on respiration and the central nervous system (10). Nonsteroidal anti- 
inflammatories (NSAIDS), which block prostaglandin-induced inflammation and edema, are an 
attractive therapeutic option because they do not result in respiratory and central nervous 
system depression, and therefore may reduce the risk of postoperative respiratory depression, 
nausea and vomiting, excessive sedation and urinary retention. NSAIDS have been shown to be 
effective analgesics after tonsillectomy (11,12). However, because their mechanism of action 
may also interfere with platelet aggregation and increase bleeding time, their use is balanced 
with concern about an increased risk of postoperative hemorrhage. Aspirin, which irreversibly 
inhibits cyclooxygenase, affects coagulation and bleeding for up to 10 days, has been associated 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
with an increased bleed rate after tonsillectomy (13). However, non-aspirin NSAIDs 
demonstrate a reversible inhibition of COX-1 and COX-2, and therefore do not have the same 
severe, prolonged effects on bleeding (14). Ibuprofen, a derivative of propionic acid, is widely 
used for musculoskeletal pain, but the study of its use for post-tonsillectomy analgesia is 
limited. 
In 2011, The American Academy of Otolaryngology published Clinical Practice Guidelines 
outlining evidence-based selection and perioperative management strategies for tonsillectomy 
in children. As part of a recommendation that clinicians educate caregivers about the 
importance of postoperative pain management, Baugh et al advocated the use of ibuprofen 
postoperatively, stating, “ibuprofen can be used safely for pain control after surgery” (15), 
citing a 2005 Cochrane Review of NSAIDs and post-tonsillectomy bleeding in support of this 
guideline (16). The Cochrane Review recently added additional studies to their analysis and 
results remained similar. The most recent Cochrane Review, published in 2010, evaluated 15 
randomized trials comparing NSAIDs with other analgesics or placebo, and determined that 
NSAID use did not significantly alter the number of perioperative bleeding episodes, both 
requiring and not requiring surgical intervention; this review did not distinguish between 
primary and secondary bleeding events (17). Because post-tonsillectomy hemorrhage is an 
uncommon event, a large number of participants is required to provide an adequate number of 
events to give a significant result, therefore the large sample size of >1000 children in the 
Cochrane Review is admirable. However, sample sizes were not adequate to compare the risk 
of bleeding with each individual NSAID. Additionally, NSAIDs were given in both oral and 
parenteral forms, as well as preoperatively, intraoperatively and postoperatively, and the 
duration of postoperative analgesic use differed between studies. The surgical technique used 
was not uniform between studies as well. It is our feeling that because of these limitations, the 
data is not sufficient to broadly implement the Academy’s recommendation that ibuprofen can 
be safely used for post-tonsillectomy analgesia without more carefully controlled, prospective 
study. 
Although there are many studies in the literature evaluating NSAID use after 
tonsillectomy, there are few randomized-prospective trials evaluating the use of ibuprofen, and 
few trials are powered to adequately assess the risk of postoperative hemorrhage. Designing 
and executing a study to specifically evaluate ibuprofen after pediatric tonsillectomy and rates 
of post-operative hemorrhage requiring return to the operating room for control is important 
to the pediatric otolaryngology community, particularly given the American Academy of 
Otolaryngology’s recent clinical guidelines. The results of such a definitive study would possibly 
affect the tens of thousands of children at risk for post-tonsillectomy hemorrhage every year. It 
would affect our own standards of care as well as national and international norms. 
 
Preliminary Studies: 
At the Massachusetts Eye and Ear Infirmary there is no precedent for administering 
ibuprofen to children after tonsillectomy with or without adenoidectomy. Despite American 
Academy of Otolaryngology support for the use of ibuprofen in the postoperative setting, 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
pediatric otolaryngologists at our institution are still hesitant to administer ibuprofen 
postoperatively without additional study of its use. 
Within the Department of Pediatric Otolaryngology at the Massachusetts Eye and Ear 
Infirmary there is a precedent for successful completion of randomized, controlled trials 
involving adenotonsillectomy (19, 20). With principal investigators dedicated to clinical 
research, as well as research nurses and coordinators at our disposal, a prospective, controlled 
clinical trial of ibuprofen use after tonsillectomy can be implemented. Additionally, the 
Massachusetts Eye and Ear Infirmary calculates annual post-tonsillectomy hemorrhage rates, 
including percentage of patients returning to the emergency room for evaluation for possible 
post-operative bleeding, as well as the percentage of patients returning to the operating room 
for control of bleeding. Thus, there is a precedent for collecting data on postoperative bleeding 
events, as well as a controlled bleed rate to which prospective study hemorrhage rates can be 
compared. 
The goal of our study is to determine if postoperative ibuprofen affects the rate of post- 
tonsillectomy hemorrhage using a non-inferiority trial design, which is intended to show that 
the effect of ibuprofen is no worse than acetaminophen, which will serve as our control. This 
differs from an equivalence trial, which aims to demonstrate that the experimental and control 
group do not differ more than a specified amount. The equivalence margin set for non- 
inferiority trials is often smaller than the treatment difference for which a placebo-controlled 
trial is powered, requiring a larger sample size. This will address two issues we have with the 
current literature evaluating NSAID use after tonsillectomy: inadequate sample size and 
unrealistic treatment differences, including up to a 20% difference in bleed rates, required to 
detect a significant difference between NSAID and control groups. Because our trial will be 
designed to test non-inferiority, the null hypothesis will assume inferiority: the objective, type 3 
bleed rate in patients treated with postoperative ibuprofen after tonsillectomy will be 
increased compared to the rate in patients given acetaminophen. 
 
 
References: 
1. Erickson BK, Larson DR, St Sauver JL, Meverden RA, Orvidas LJ. Changes in incidence and 
indications of tonsillectomy and adenotonsillectomy, 1970-2005. 
2. Bluestone CD. Current indications for tonsillectomy and adenoidectomy. Ann Otol 
Rhinol Laryngol Suppl 1992; 155:58-64. 
3. Berkowitz RG, Zalzal GH. Tonsillectomy in children under 3 years of age. Arch 
Otolaryngol Head Neck Surg 1990; 116:685-6. 
4. Tom LWC, DeDio RM, Cohen DE, et al. Is outpatient tonsillectomy appropriate for young 
children? Laryngoscope 1992; 102:277-80. 
5. Ross AT, Kazahaya K, Tom LW. Revisiting outpatient tonsillectomy in young children. 
Otolaryngol Head Neck Surg 2003; 128:326-31. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
6. National Center for Health Statistics, Centers for Disease Control, Advance data 283: 
ambulatory surgery in the United States, 1994. National Center for Health Statistics. Available 
on the Web at www.cdc.gov/nchs. 
7. National Health Statistics Reports, Centers for Disease Control, Ambulatory Surgery in 
the United States, 2006. Number 11, January 28, 2009–Revised September 4, 2009. Available 
on the Web at www.cdc.gov/nchs. 
8. Randall DA, Hoffer ME. Complications of tonsillectomy and adenoidectomy. Otolaryngol 
Head Neck Surg. 1998; 118:61-8. 
9. Blakley BW. Post-tonsillectomy bleeding: How much is too much? Otolaryngol Head 
Neck Surg 2009; 140:288-290. 
10. Huasband AD, Davis A. Pain after tonsillectomy. Clin Otolaryngol 1996; 21: 99-101. 
11. Harley EH, Dattolo RA. Ibuprofen for tonsillectomy pain in children: Efficacy and 
complications. Otolaryngol Head Neck Surgy 1998; 119(5): 492-496. 
12. St. Charles CS, Matt BH, Hamilton MM, Katz BP. A comparison of ibuprofen 
versus acetaminophen with codeine in the young tonsillectomy patient. Otolaryngol Head Neck 
Surg 1997; 117(1): 76-82. 
13. Reuter SH, Montgomery WW. Aspirin vs acetaminophen after tonsillectomy. Arch 
Otolaryngol Head Neck Surg 1964; 80: 214-17. 
14. Schaefer AI. Effects of nonsteroidal anti-inflammatory drugs on platelet function and 
systemic hemostasis. J Clin Pharmacol 1995; 35: 209-19. 
15. Baugh RF, Archer SM, Mitchell RB, Rosenfeld RM et al. Clinical practice guideline: 
tonsillectomy in children. Otolaryngol Head Neck Surg 2011: 144(IS): S1-S30. 
16. Cardwell ME, Siviter G, Smith AF. Non-steroidal anti-inflammatory drugs and 
perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2005; (2): 
CD003591. 
17. Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti-inflammatory drugs and 
perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2010; (10): CD 
18. Brigger MT, Cunningham MJ, Hartnick CJ. Dexamethasone administration and 
postoperative bleeding risk in children undergoing tonsillectomy. Arch Otolaryngol Head Neck 
Surg 2010; 136(8): 766-72. 
19. Lister MT, Cunningham MJ, Williams BB, Tirell A, Schaumberg DA, Hartnick CJ. 
Microdebrider tonsillotomy vs electrosurgical tonsillectomy: a randomized, double-blind, paired 
control study of postoperative pain. Arch Otolaryngol Head Neck Surg 2006; 132(6): 599-604. 
20. Collison PJ, Mettler B. Factors associated with post-tonsillectomy hemorrhage. Ear 
Nose Throat 2000; 79(8): 641-49. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
1.2 Rationale 
Nonsteroidal anti-inflammatories (NSAIDs) block prostaglandin-induced inflammation 
and edema. They are an attractive alternative to narcotic analgesics because they do not cause 
respiratory or central nervous system depression. NSAIDs previously have been shown to be 
effective for the control of post-tonsillectomy pain. However, because of reversible COX-1 and 
COX-2 inhibition, there is concern that ibuprofen and other NSAIDs may temporarily inhibit 
platelet aggregation and increase risk of bleeding postoperatively. A recently published 
Cochrane metaanalysis demonstrated there is no increased risk of postoperative hemorrhage, 
however, and the American Academy of Otolaryngology has endorsed the use of ibuprofen as 
an analgesic in patients undergoing adenotonsillectomy. Ibuprofen is used widely in the 
pediatric population, both for treatment of musculoskeletal pain as well as an anti-pyretic. 
Ibuprofen is an NSAID formulation that is commonly used and widely available, domestically 
here in the US as well as internationally. 
For this study, we feel it is important to evaluate the effect of ibuprofen on post- 
tonsillectomy hemorrhage and pain control by dosing the drug in a similar way to how it would 
be used in the community. Other studies of NSAIDs and tonsillectomy gave investigational 
drugs parenterally, or in one to two doses in the immediate postoperative period. Therefore, 
we do not feel the results of these previous studies can be generalized to the effects of NSAID 
use throughout the postoperative period. The highest risk of bleeding after tonsillectomy is 
roughly 1 week from surgery, and we are interested in evaluating how NSAID use during this 
time period may affect bleeding risk as well. Additionally, previous studies have shown that 
significant postoperative pain extends up to 8 days after surgery. Therefore, we have designed 
to study so that ibuprofen is taken orally at the maximum dose, just as acetaminophen is often 
maximally dosed in the postoperative period in these patients, 10mg/kg, and for 9 days (the 
day of surgery and eight postoperative days). 
This study will evaluate the effects of ibuprofen on postoperative bleeding and pain in 
children aged 2-18 years. Children undergoing tonsillectomy with or without adenoidectomy 
with electrocautery for recurrent tonsillitis and sleep disordered breathing/OSA will be eligible 
to participate. We will exclude children with NSAID or aspirin allergy, acetaminophen allergy 
(our control), bleeding disorders, asthma, lung, kidney or liver disease, or allergy to the dyes 
used in the medications used. 


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2. STUDY OBJECTIVES 
 
 
2.1 Primary Objective 
Aim 1: To compare the rates of post-tonsillectomy bleeding between pediatric patients who 
receive postoperative ibuprofen to those who receive acetaminophen in a prospective, 
randomized, blinded and controlled trial. 
The primary objective of this study is to determine if postoperative ibuprofen at 10mg/kg 
dosed QID (four times daily, roughly Q6 hours) postoperatively for 9 days is associated with an 
increased rate of post-tonsillectomy bleeding requiring operative intervention for hemostasis in 
children when compared with acetaminophen. To achieve this, rates of post-tonsillectomy 
bleeding, both primary, defined as occurring < 24 hours after surgery, and secondary, defined 
as occurring > 24 hours after tonsillectomy, will be recorded. Additionally, distinction will be 
made between bleeds requiring emergency room evaluation, admission for observation, and 
operative control of hemorrhage. 
 
2.2 Secondary Objective(s) 
Aim 2: To compare the rates of post-tonsillectomy hemorrhage when studying different groups 
of patients based upon their age, indication for tonsillectomy, or operating surgeon. 
The second objective of this study is to determine if bleeding rates differ according to 
surgical indication, age of the patient, or operating surgeon, using a multi-variate logistic 
regression model. This is important since indication for tonsillectomy varies in children. 
Younger children tend to undergo tonsillectomy for obstructive sleep symptoms whereas older 
children tend to undergo tonsillectomy for infectious tonsillitis. 
 
Aim 3: To evaluate effectiveness of ibuprofen as a post-tonsillectomy analgesic in comparison 
to Acetaminophen, which is currently the standard of care at our institution. 
The third objective of this study is to evaluate the efficacy of ibuprofen at 10mg/kg dosing 
(max dose 600mg) at QID dosing as an analgesic in the postoperative period in comparison to 
Acetaminophen, 15mg/kg (max dose 650mg), which is currently the standard of care at our 
institution. Previous studies have determined that ibuprofen at 5mg/kg dosing is an effective 
post-tonsillectomy analgesic, however 10mg/kg dosing, the maximum ibuprofen dose, has not 
been previously evaluated in the literature. We feel it is important to evaluate both the 
analgesic effect and rate of post-tonsillectomy bleeding associated with this maximum dosing if 
ibuprofen is to be widely used in the postoperative period after tonsillectomy. 


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3. STUDY DESIGN 
 
 
3.1 Study Design Description 
 
Recruitment: Patients will be recruited from the practices of Drs. Hartnick, Keamy, Setlur, and 
Cohen and Diercks (starting 9/1/16) (The Massachusetts Eye and Ear Infirmary), as well as Drs. 
Boseley and Rogers (Madigan Army Base; Tacoma, WA), Brigger and Gaudreau (Naval Medical 
Center of San Diego, Department of Otolaryngology; San Diego, CA), Maturo (Brooke Army 
Medical Center, Department of Otolaryngology; San Antonio, TX), and Gallagher (Naval Medical 
Center, Department of Otolaryngology; Portsmouth, VA). Over the last two years, the average 
annual number of pediatric tonsillectomies for each collaborating investigator was 
approximately 200. Informed consent will be obtained for the study by the principal 
investigator, co-investigators, or research nurses at the time of the preoperative visit or on the 
day of surgery prior to arrival in the preoperative area. 
 
Inclusion criteria: Patients ages 2-18 undergoing tonsillectomy with or without adenoidectomy 
by electrocautery alone for sleep disordered breathing or infectious tonsillitis. Patients with 
complex medical conditions and craniofacial abnormalities will be included. Only patients who 
are not pregnant will be included. Informed consent and child assent will be required for 
enrollment. 
 
Exclusion criteria: Patients with a known personal or family history of a bleeding disorder will 
be excluded. Patients with a history of asthma, kidney or liver problems will also be excluded. 
Patients with tonsillectomy or adenoidectomy performed using a cold knife technique, 
microdebrider, coblation or plasma knife. Patients on NSAIDs for other medical conditions, or 
those who have taken NSAIDs within 1 week of surgery will be excluded. Patients with allergy 
to aspirin or other NSAIDs, acetaminophen, Red Dye #40 or Red Dye #33 will also be excluded. 
Patients on oral steroids will be excluded. Pregnancy testing using urine beta-HCG will be 
performed on all children > 13 years of age, or those younger than 13 who are menstruating. 
Patients found to be pregnant will be excluded from participation. Patients and parents who 
are unable to understand study instructions will be excluded. Patients unwilling to enroll in the 
study will have the tonsillectomy with or without adenoidectomy performed according to 
current practice standards. 
 
Randomization: Patients will be randomized upon enrollment after obtaining informed 
consent, and assent when indicated. Randomization will be performed centrally by the 
Massachusetts Eye and Ear Infirmary pharmacy, and groups of randomization schemes will be 
distributed to the pharmacies of participating institutions. The MEEI pharmacy randomization 
scheme will occur via a one-to-one scheme generated based on a uniform (1, 2) random 
number generator using “Research Randomizer,” which is available online at 


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www.randomizer.org. 722 random number assignments were generated based on an 
anticipated n = 722. So far, MEEI has been assigned numbers 1-400, San Diego is assigned 401- 
500, and Madigan is assigned numbers 601-700. Initially Madigan had received numbers 501- 
600, however prior to enrollment there was a breach in blinding of this scheme, so the study 
numbers were thrown out and additional numbers were dispensed to the site. 
 
Blinding: The surgeon, nurses, and patient/parent will be blinded regarding to which arm the 
patient has been randomized. The pharmacy of each institution will dispense grape-flavored 
ibuprofen 100mg/5mL (Leader) or grape-flavored acetaminophen 160mg/5mL (Leader) 
based upon the arm to which each participant has been randomized. Ibuprofen will be dosed 
at 10mg/kg (max dose 600mg) and acetaminophen at 15mg/kg (max dose 650mg), dosing for 
each will be QID (roughly Q6 hours, however we left dosing QID to allow for some flexibility in 
the dosing schedule to accommodate patient sleeping schedules). The pharmacy will 
manipulate the volume of each medication using Ora Blend suspension so that for each child, 
weight based dosing of each medication will be equivalent in volume. Volume manipulation 
tables are provided in Appendix A. For each child, an amber colored bottle of 36 doses of study 
medication will be prepared. The bottle will indicate the patient’s name, medical record 
number, and the volume to be given for each dose of medication. The first dose of study 
medication will be dispensed 4 hours after the preoperative acetaminophen dose. Thereafter, 
medication will be dosed QID (or roughly 6 hours apart). 
 
At Portsmouth, San Diego and MEEI Sites: nursing staff will draw up study medication in study 
supplied amber colored syringes from the bottle of study medication. Upon discharge, the 
patients will be discharged with remaining medication in the bottle, as well as 2 amber colored 
syringes to draw up medication at home. 
 
At Madigan: Due to nursing regulations, nurses at this institution are not authorized to draw up 
study medication. At this institution, at the time of enrollment a bottle of study medication 
containing 36 doses will be prepared. While children remain in house, the pharmacy will draw 
study medication into an amber colored syringe from the bottle. At the time of discharge, 
patients will be discharged with the bottle of remaining study medication and 2 amber colored 
syringes to draw up the medication at home. 
 
Surgical technique: All patients will be administered 15mg/kg (max dose 650mg) of 
acetaminophen preoperatively prior to arrival in the preoperative area. General anesthesia will 
be administered, left to the discretion of each anesthesiologist. After induction, prior to 
surgical commencement, the patients will receive corticosteroids, either IV dexamethasone 
0.5mg/kg (maximum dose of 8mg) or IV methylprednisolone (Solu-Medrol) 2.5mg/kg (max 
dose 40mg), which is the standard of care at MEEI. The administration of intraoperative 
steroids not only reduces postoperative edema, but has also been shown to decrease 
postoperative nausea and vomiting. 


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The standard method of tonsillectomy among participating surgeons will be 
extracapsular monopolar electrocautery with standard settings of 12 watts (fulgurate) using a 
spatula tip. Bleeding will be controlled with suction cautery on a setting of 12-18 watts 
(fulgurate). Adenoidectomy will be performed at 30 watts (fulgurate). Anesthetic technique, 
perioperative analgesia with narcotics, and post-operative care will remain equivalent between 
the two study arms. Antibiotics will not be administered in the perioperative period. 
Postoperative anti-emetic therapy will be standardized by all collaborating physicians using 
standardized order sets. 
 
Postoperative period: 
 
No Postoperative Antibiotic Prophylaxis: 
 
Postoperative antibiotics will not be administered based upon the American Academy of 
Otolaryngology’s strong recommendation that antibiotics no longer be used for postoperative 
prophylaxis after adenotonsillectomy (15). For the first 8 postoperative days (9 days total, 
POD0-9), children will be administered around the clock, weight based analgesia from 
medication provided by the inpatient pharmacy at each site. 
 
Postoperative Anti-Emetic Plan: 
 
The following plan for anti-emetics will be used for symptomatic children while hospitalized 
prior to discharge. No anti-emetics will be administered on an outpatient bases: Ondansetron 
0.1mg/kg (max dose 4mg) IV Q8 hours prn nausea/vomiting and/or promethazine 0.25mg/kg IV 
Q6 hours prn nausea/vomiting. 
 
Postoperative Analgesia: 
 
The pharmacy of each institution will dispense grape-flavored ibuprofen 100mg/5mL (Leader) 
or grape-flavored acetaminophen 160mg/5mL (Leader) based upon the arm to which each 
participant has been randomized. Ibuprofen will be dosed at 10mg/kg (max dose 600mg) and 
acetaminophen at 15mg/kg (max dose 650mg), dosing for each will be QID (roughly Q6 hours, 
however we left dosing QID to allow for some flexibility in the dosing schedule to accommodate 
patient sleeping schedules). The pharmacy will manipulate the volume of each medication 
using Ora Blend suspension so that for each child, weight based dosing of each medication will 
be equivalent in volume. Volume manipulation tables are provided in Appendix A. For each 
child, an amber colored bottle of 36 doses of study medication will be prepared. The bottle will 
indicate the patient’s name, medical record number, and the volume to be given for each dose 
of medication. The first dose of study medication will be dispensed 4 hours after the 
preoperative acetaminophen dose. Thereafter, medication will be dosed QID (or roughly 6 
hours apart). Surgeons, nursing staff, and patients and their families will be blinded regarding 
the type of medication administered (acetaminophen vs. ibuprofen). 


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At Portsmouth, San Diego and MEEI Sites: nursing staff will draw up study medication in study 
supplied amber colored syringes from the bottle of study medication. Upon discharge, the 
patients will be discharged with remaining medication in the bottle, as well as 2 amber colored 
syringes to draw up medication at home. 
 
At Madigan: Due to nursing regulations, nurses at this institution are not authorized to draw up 
study medication. At this institution, at the time of enrollment a bottle of study medication 
containing 36 doses will be prepared. While children remain in house, the pharmacy will draw 
study medication into an amber colored syringe from the bottle. At the time of discharge, 
patients will be discharged with the bottle of remaining study medication and 2 amber colored 
syringes to draw up the medication at home. 
 
Acetaminophen will be given as 15mg/kg dosing (maximum dose 650mg) and ibuprofen will be 
given as 10mg/kg dosing (maximum dose 600mg). Children with breakthrough pain eligible for 
narcotics (based upon age, OSA status) will receive weight based doses of oxycodone 1mg/1mL 
elixir (0.05-0.1mg/kg) as well as be prescribed oxycodone to use for breakthrough pain as an 
outpatient. After 9 days, patients will be instructed to take acetaminophen 15mg/kg (max dose 
650mg) every 4-6 hours as needed for breakthrough pain. They will be instructed not to use 
nonsteroidal anti-inflammatory drugs (NSAIDS) in the postoperative period (14 days). 
 
Weight based ibuprofen dosing of 10mg/kg was chosen because it is the maximum dose of this 
medication. Previous studies evaluating ibuprofen use after tonsillectomy used ibuprofen at 
5mg/kg (11,12). If ibuprofen is to be used for post-tonsillectomy analgesia, it would likely be 
used at the maximum dose, similar to the maximum dose of Acetaminophen (15mg/kg) already 
used in standard practice at our institution. Therefore, we argue that before this practice is 
instituted, both the analgesic effect as well as the risk of postoperative hemorrhage associated 
with this dosing need to be further characterized. 
 
The decision to recommend around the clock dosing of analgesics for 9 days was chosen based 
upon previous studies which indicate that postoperative pain after extracapsular tonsillectomy 
using electrocautery persists above 2 on the faces pain scale-revised (range 0-6) through POD7 
(19). Additionally, studies of postoperative bleeding indicate that the highest risk of incidence 
of postoperative bleeding occurs on postoperative day 8 (20). Therefore, in order to assess the 
rate of bleeding associated with ibuprofen use, it seems reasonable to administer the drug 
throughout the period associated with greatest risk. 
 
A postoperative recommendation form will be placed on each chart for review by the nurses in 
the recovery room and on the floor (if inpatient status). This form will state that no additional 
acetaminophen be administered to the participant, and instructing that analgesia be 
administered from study supplied medication or supplemental narcotics if indicated for 
breakthrough pain at the discretion of participating surgeons. It will also have standard anti- 
emetic medications listed. 


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Pain control data will be collected using a standardized, validated questionnaires as well as 
additional questions regarding postoperative pain control and return to normal diet and sleep 
patterns (see attachment at end of proposal). These questionnaires have been used in previous 
studies evaluating ibuprofen and post-tonsillectomy pain (11, 12). Questionnaires for each 
postoperative day, as well as a 9 day supply of medication, will be dispensed at discharge. 
Patient’s caregivers will be asked to complete the questionnaire on a daily basis for the day of 
surgery and first eight postoperative days, and bring it, as well as any remaining study 
medication, to the postoperative visit for review. Remaining syringes will be assessed to 
determine the total number of doses of medication each patient received over the 9 day 
postoperative period. 
 
All participating children and their parents will be advised to see medical evaluation emergently 
should a bleeding event occur, as is currently standard practice after adenotonsillectomy. All 
children with evidence of a bleed, such as a history of bleeding, active bleeding, or an 
oropharyngeal clot will be admitted, at least, for observation, at the discretion of participating 
surgeons. A large bore IV will be placed and IV fluids administered. Children with active 
bleeding or a large oropharyngeal clot will return to the operating room, at the discretion of the 
participating clinician, for control of hemorrhage under general anesthesia and endotracheal 
intubation. They will be instructed to discontinue the study drug, and take acetaminophen 
15mg/kg (maximum dose 650mg) every 4-6 hours for pain control. Children prescribed 
oxycodone for pain control postoperatively will be able to continue narcotics as well. 
 
At the end of the 14 day postoperative period, a study physician or participating research nurse 
will conduct a postoperative bleeding questionnaire during the postoperative visit. If a 
postoperative visit is not planned, investigators will contact patients’ parents/guardians to 
question about postoperative bleeding events. In cases where bleeding occurred, the written 
and electronic hospital events will be evaluated for further information. Bleeding events will be 
classified according to the type of intervention taken. 
 
Results will be recorded in an Excel spreadsheet, the latest design of which was approved 
during the MEEI IRB approval on 5.1.12. 
3.2 Allocation to Treatment 
Study subjects will be assigned to either the ibuprofen or acetaminophen arm based on a 
randomization scheme generated by the MEEI pharmacy and distributed to all participating site 
pharmacies. When a child is enrolled at each site, the pharmacy will assign the child a study 
number attached to a randomized number (1 or 2), which dictates to which arm the child will 
be assigned. See below, under “Randomization Procedures” for further details. 
3.2.1 Randomization Procedures 
Patients will be randomized upon enrollment after obtaining informed consent, and assent 
when indicated. Randomization will be performed centrally by the Massachusetts Eye and Ear 
Infirmary pharmacy, and groups of randomization schemes will be distributed to the 


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pharmacies of participating institutions. The MEEI pharmacy randomization scheme will occur 
via a one-to-one scheme generated based on a uniform (1, 2) random number generator using 
“Research Randomizer,” which is available online at www.randomizer.org.  722 random 
number assignments were generated based on an anticipated n = 722. So far, MEEI has been 
assigned numbers 1-400, San Diego is assigned 401-500, and Madigan is assigned numbers 601- 
700. Initially Madigan had received numbers 501-600, however prior to enrollment there was a 
breach in blinding of this scheme, so the study numbers were thrown out and additional 
numbers were dispensed to the site. 
 
3.2.2 Masking Procedures 
The surgeon, nurses, and patient/parent will be blinded regarding to which arm the patient has 
been randomized. Only the pharmacy will know the group to which each study participant has 
been assigned. The surgeon, nurses, and patients/parents will be blinded regarding to which 
arm the patient has been randomized. The volume of acetaminophen will be manipulated by 
each participating pharmacy using OraBlend solution so that the weight-based dose of 
ibuprofen and acetaminophen are equivalent in volume. The schedule for mixing medication is 
provided in Appendix A. 
 
3.2.3 Breaking the Mask 
If a study patient receives ibuprofen or acetaminophen while taking the study medication, 
either because of a parental decision or medication error, the study medication will be 
discontinued. The participating institution’s pharmacy will be contacted and the study 
unblinded for the study subject in question. If concern for overdosing of acetaminophen, liver 
function tests will be performed, and if concern for overdosing of ibuprofen, kidney function 
will be testing using BUN and Creatinine. 
If a bleeding event occurs, subjects should discontinue the study medication. This will be 
emphasized verbally at the time of consent and discharge. Additionally, study-specific 
postoperative instruction sheets will be distributed that also remind parents to discontinue the 
study medication should a bleeding event occur. After discontinuing the study medication, 
parents should start acetaminophen 15mg/kg (max dose 650mg) every 4-6 hours as needed for 
pain. If children are prescribed oxycodone 1mg/kg for breakthrough pain, they may continue 
this medication. 
Patients with bleeding enrolled in the study will be managed in the same fashion as children 
who are not enrolled, therefore unblinding will not be necessary in the case of each bleeding 
event. 


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4. SUBJECT SELECTION 
 
 
4.1 Subject Inclusion Criteria 
• Patients ages 2-18 undergoing tonsillectomy with or without adenoidectomy by electrocautery 
alone for sleep disordered breathing or infectious tonsillitis. 
• Patients with complex medical conditions and craniofacial abnormalities will be included. 
• Family must understand and be able to read English. 
• Only patients who are not pregnant will be included. 
• Informed consent and, when appropriate, child assent will be required for enrollment. 
4.2 Subject Exclusion Criteria 
• Patients with a known personal or family history of a bleeding disorder will be excluded. 
• Patients with a history of asthma, kidney or liver problems will also be excluded. 
• Patients with tonsillectomy or adenoidectomy performed using a cold knife technique, 
microdebrider, coblation or plasma knife. 
• Patients on NSAIDs for other medical conditions or those who have taken NSAIDs within 1 week 
of surgery will be excluded. 
• Patients with allergy to aspirin or other NSAIDs, acetaminophen, Red Dye #40 or Red Dye #33 
will also be excluded. 
• Pregnancy testing using urine beta-HCG will be performed on all children > 13 years of age, or 
those younger than 13 who are menstruating; this is the testing protocol used at the Children’s 
Hospital of Boston. Patients found to be pregnant will be excluded from participation. 
• Patients unwilling to enroll in the study will have the tonsillectomy with or without 
adenoidectomy performed according to current practice standards. 


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5. STUDY DRUG(S)/DEVICE(S) 
 
 
5.1 Study Drug/Device Information 
The pharmacy of each institution will dispense grape-flavored ibuprofen 100mg/5mL (Leader) 
or grape-flavored acetaminophen 160mg/5mL (Leader) based upon the arm to which each 
participant has been randomized. Ibuprofen will be dosed at 10mg/kg (max dose 600mg) and 
acetaminophen at 15mg/kg (max dose 650mg), dosing for each will be po QID (4 times daily). 
The pharmacy will manipulate the volume of acetaminophen using Ora Blend suspension so 
that for each child, weight based dosing of acetaminophen and ibuprofen will be equivalent in 
volume. See Appendix A for Acetaminophen/OraBlend and Ibuprofen mixing schedules. The 
first dose will be given 4 hours after the preoperative dose of acetaminophen (15mg/kg, max 
dose 650mg), then QID (roughly Q6 hours) thereafter for a total of 9 days (the day of surgery 
and then the first 8 postoperative days, for a total of 36 doses). 
 
5.2 Study Drug/Device Compliance/Adherence 
Study subjects will be given instructions about dosing at the time of consent, discharge from 
the hospital, and in writing on the postoperative instruction sheet. They will be instructed to 
record administration of each dose of study medication on a dosing sheet, which is provided at 
the top of each day’s postoperative medication and pain questionnaire sheet. At the 
postoperative visit, the dosing and pain questionnaire sheet will be returned for review. 
Additionally, any remaining study medication will be collected. The remaining volume of 
medication will be measured and compared to the volume of each weight-based dose for the 
study subject. This will allow us to calculate the number of doses actually given. 
 
At the postoperative visit, a study questionnaire will be administered during which patients 
and their families are asked about whether the study medication was self-discontinued, and 
whether acetaminophen or ibuprofen were administered during the study period. This 
information will be recorded. 
 
As we plan to analyze the data using an intention to treat analysis, study subjects that are 
withdrawn from the study will not be replaced. 
 
5.3 Study Drug Supplies 
 
• Formulation and Packaging 
 
The pharmacy of each institution will dispense grape-flavored ibuprofen 100mg/5mL (Leader) 
or grape-flavored acetaminophen 160mg/5mL (Leader) based upon the arm to which each 


Massachusetts Eye and Ear Infirmary 
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participant has been randomized. Ibuprofen will be dosed at 10mg/kg (max dose 600mg) and 
acetaminophen at 15mg/kg (max dose 650mg), dosing for each will be po QID (4 times daily). 
The pharmacy will manipulate the volume of acetaminophen using Ora Blend suspension so 
that for each child, weight based dosing of acetaminophen and ibuprofen will be equivalent in 
volume. See Appendix A for Acetaminophen/OraBlend and Ibuprofen mixing schedules. An 
expiration date 9 days after study enrollment will be specified to further emphasize that the 
study medication should not be given after the 8th postoperative day. 
 
At the time of enrollment, 36 weight based doses, calculated to the nearest kilogram, of study 
medication will be prepared and dispensed in amber colored bottles. Each bottle will be 
identified by the patient’s name, medical record number and instructions regarding the volume 
of medication to be dispensed for each dose. The pharmacy will also dispense two amber 
colored syringes from which the medication can be drawn up from the study bottle and volume 
of each dose measured. 
• Preparing and Dispensing 
 
The pharmacy at each participating institution will prepare 36 weight based doses of the study 
medication (dosages specified above).  To allow for adequate blinding, OraBlend suspension 
will be added to acetaminophen so that the weight based volume is equivalent to the weight 
based volume of ibuprofen. The mixing scheme is provided in Appendix A. Medication will be 
dispensed in an amber colored bottle with 2 amber colored syringes for drawing up and 
measuring the volume of each dose of medication. The first dose of study medication will be 
dispensed 4 hours after the preoperative dose of acetaminophen. Thereafter, study medication 
will be dispensed QID (four times daily, roughly Q6 hours) 
 
At Portsmouth, San Diego and MEEI Sites: Nursing staff will draw up study medication in study 
supplied amber colored syringes from the bottle of study medication. Upon discharge, the 
patients will be discharged with remaining medication in the bottle, as well as 2 amber colored 
syringes to draw up medication at home. 
 
At Madigan: Due to nursing regulations, nurses at this institution are not authorized to draw up 
study medication. At this institution, at the time of enrollment a bottle of study medication 
containing 36 doses will be prepared. While children remain in house, the pharmacy will draw 
study medication into an amber colored syringe from the bottle. At the time of discharge, 
patients will be discharged with the bottle of remaining study medication and 2 amber colored 
syringes to draw up the medication at home. 
 
• Administration 


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The first dose of study medication will be dispensed 4 hours after the preoperative dose of 
acetaminophen. Thereafter, study medication will be dispensed QID (four times daily, roughly 
Q6 hours) 
 
At Portsmouth, San Diego and MEEI Sites: Nursing staff will draw up study medication in study 
supplied amber colored syringes from the bottle of study medication. Upon discharge, the 
patients will be discharged with remaining medication in the bottle, as well as 2 amber colored 
syringes to draw up medication at home. 
 
At Madigan: Due to nursing regulations, nurses at this institution are not authorized to draw up 
study medication. At this institution, at the time of enrollment a bottle of study medication 
containing 36 doses will be prepared. While children remain in house, the pharmacy will draw 
study medication into an amber colored syringe from the bottle. At the time of discharge, 
patients will be discharged with the bottle of remaining study medication and 2 amber colored 
syringes to draw up the medication at home. 
 
5.4 Study Drug/Device Storage and Accountability 
• During hospitalization, the study medication at Portsmouth, San Diego, and MEEI will be kept in 
Pyxis medication storage systems and accessed when the study medication administration is 
due. 
• During hospitalization at Madigan, the study medication will remain in the inpatient pharmacy 
so that each dose of study medication can be drawn up and dispensed when administration is 
due (at this site the nursing staff is not authorized to draw the dose up from a larger volume of 
medication). 
• At home, patients will store the study medication at room temperature. Any remaining 
medication should be returned at the postoperative visit. At that time the volume of remaining 
medication will be measured, and the medication will be discarded. The study medication label 
will indicate an expiration date 9 days after patient enrollment. If study medication is not 
returned, patients are instructed to discard the medication. 
 
5.5 Other Medications 


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• Administration: 
 
All study subjects will receive 15mg/kg (max dose 650mg) of acetaminophen orally in the 
preoperative area. After induction, they should receive IV dexamethasone 0.5mg/kg (maximum 
dose of 8mg) or IV methylprednisolone (Solu-Medrol) 2.5mg/kg (max dose 40mg).  If the 
patient is eligible to receive postoperative narcotics for breakthrough pain, they may be 
prescribed oxycodone 1mg/1mL elixir (0.05-0.1mg/kg) in addition to the study medication. 
They should not receive antibiotic prophylaxis at the time of surgery or during the 
postoperative period. They may receive Ondansetron 0.1mg/kg (max dose 4mg) IV Q8 hours 
prn nausea/vomiting and/or promethazine 0.25mg/kg IV Q6 hours prn nausea/vomiting while 
hospitalized. No antiemetics should be administered at home. 
 
• Rescue Medication or Therapy 
 
If study subjects do not have adequate pain control on the study medication and oxycodone 
elixir, when eligible to receive this medication, they may be removed from the study and given 
another narcotic for postoperative pain. Any children removed from the study for this reason 
will be recorded. 


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6. BIOSPECIMEN COLLECTION (IF APPLICABLE) 
 
 
Biospecimen collection is not applicable for this study. 


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7. STUDY PROCEDURES 
 
 
7.1 Screening Procedures 
Subjects will be identified when they are scheduled for a tonsillectomy and approached to 
participate in this study. Their electronic medical record will be reviewed to confirm they meet 
inclusion criteria and do not meet exclusion criteria. If they meet all inclusion criteria and none 
of the exclusion criteria, subjects will be asked to participate in the study. 
7.2 Enrollment/Baseline Procedures 
The study will be introduced to the patients and his or her family at time the tonsillectomy is 
scheduled. The Principal Investigator of each participating site will introduce the study and 
answer any questions patients and their families may have. On the day of surgery, 
investigators will reapproach patients and their families about enrollent. They will be given the 
opportunity to consider participation prior to arrival in the preoperative area. Only those who 
sign an informed consent form before surgery will be included in the study. 
Written, informed consent will be obtained from the parent or guardian of each participating 
child under the age of 18. Children 18 years of age will sign their own informed consent. Only 
personnel approved by each participating center’s IRB will obtain consent. Personnel will be 
available to answer any questions that participants and their families may have. 
Consent may be obtained at the preoperative visit or on the day of surgery preoperatively. If 
consent is obtained during the preoperative visit, procedures will be reviewed with the child 
and their parent on the day of surgery to confirm their willingness to participate. 
Obtaining written assent will be considered for all children over the page of 12. As each child’s 
degree of maturity will vary, whether or not to obtain written assent will be left to the 
discretion of personnel obtaining consent. In the assent form, children will be notified that a 
urine sample for pregnancy testing will be requested for all female participants > 13 years of 
age and/or are menstruating. 
 
A colored piece of paper identifying the patient’s study participation and postoperative 
guidelines will be placed on the front of each participant’s chart. This will be used to guide 
nurses and responding clinicians in their management of participating patients. 
 
Date of Surgery 
1. Pre-Anesthesia Unit: All subjects should receive a preoperative dose of acetaminophen 
15mg/kg (max dose 650mg) by mouth in the preoperative waiting area prior to surgery. 


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2. Intraoperative Anesthesia: Subjects will undergo endotracheal intubation and general 
anesthesia. The type of anesthesic agents administered to each child will be left to the 
discretion of participating anesthesiologists. No standard anesthesia plan will be used as 
children’s needs may be vary intraoperatively. However, children will be administered 
intraoperative steroids and will not receive intraoperative or postoperative antibiotics. 
 
a. Steroid administration. The administration of intraoperative steroids not only 
reduces postoperative edema, but has also been shown to decrease postoperative 
nausea and vomiting. After induction, all children should be administered 
dexamethasone (Decadron) 0.5mg/kg (max dose 8mg) IV OR methylprednisolone 
(Solu-Medrol) 2.5mg/kg (max dose 40mg) IV. 
 
b. No antibiotics will be administered intraoperatively or in the postoperative period. 
This is based upon recently published post-tonsillectomy guidelines published by the 
American Academy of Otolaryngology. 
 
3. Surgical Technique 
a. Tonsillectomy: The standard method of tonsillectomy among participating surgeons 
will be extracapsular monopolar electrocautery with the standard settings of 12 
watts fulgurate using a spatula tip. 
b. Hemostasis: Bleeding will be controlled with a suction cautery on a setting of 12-18 
watts fulgurate. 
c. Adenoidectomy: The standard method of adenoidectomy with suction cautery will 
be performed at 30 watts fulgurate. 
 
4. Post-Anesthesia Care: Children will receive standard postoperative care in the recovery 
room; the agents used will be left to the discretion of participating anesthesiologists. In this 
setting, children may receive antiemetics and additional narcotics if needed. However, 
acetaminophen will not be administered postoperatively.  Four hours after the 
preoperative dose of acetaminophen, children may start receiving the study drug. 
 
5. Postoperative Anti-emetic Plan: The following plan for anti-emetics will be used for 
symptomatic children while hospitalized prior to discharge. No anti-emetics will be 
administered on an outpatient bases: Ondansetron 0.1mg/kg (max dose 4mg) IV Q8 hours 
prn nausea/vomiting and/or promethazine 0.25mg/kg IV Q6 hours prn nausea/vomiting. 
 
 
7.3 Study Drug or Device Procedures 
a. The pharmacy of each institution will dispense grape-flavored ibuprofen 100mg/5mL 
(Leader) or grape-flavored acetaminophen 160mg/5mL (Leader) based upon the 
arm to which each participant has been randomized. Ibuprofen will be dosed at 


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10mg/kg (max dose 600mg) and acetaminophen at 15mg/kg (max dose 650mg). 36 
doses of the study medication will be prepared and dispensed in an amber colored 
bottle with two amber colored syringes. The first dose will be given 4 hours after the 
preoperative acetaminophen dose. Thereafter, the study medication will be given QID. 
 
b. Whether or not a child is also eligible to receive narcotic medication for breakthrough 
pain will be left to the discretion of each participating care-giver. 
i. If narcotics are to be given, children should receive oxycodone 1mg/1mL elixir at 
0.05-0.1mg/kg dosing every 4-6 hours. 
ii. Oxycodone may be given while the child is an inpatient, as well as prescribed for 
home use. 
iii. If narcotics are given, children should also continue to receive the study drug 
four times daily (QID). 
c. Subjects should continue the study medication four times daily (QID) on the day of 
surgery, as well as the first 8 postoperative days (9 days total). They should continue 
until study medication supplies have been exhausted, unless study medication remains 
after postoperative day 8. After this time, the study patient should receive 
acetaminophen 15mg/kg (max dose 50mg) every 4-6 hours as needed for pain. If the 
child was prescribed oxycodone elixir postoperatively they may continue this 
medication as well. 
d. Parents’ family members will be asked to fill out study medication dosing and pain 
control questionnaires each day, starting on postoperative day 0, the day of surgery, 
even if the child remains a patient on the in-patient ward, through postoperative day 8. 
e. Study subjects and their parents should be asked to save any unused study medication, 
and to bring the bottle to their postoperative visit for collection along with medication 
dosing and pain questionnaires. 
 
Pain control Data Acquisition 
1. Patients and their family members will receive a packet of 9 study medication dosing and 
pain control questionnaires along with the study drug, and will be instructed to fill out this 
questionnaire at the end of each postoperative day (9 days total, postoperative day 0-8). 
See Appendix B. 
2. Study subjects and their parents will be asked to bring these questionnaires to their first 
postoperative visit for collection. 
3. Study subjects will also be asked to the bottle of any remaining study medication. This will 
allow study personnel to assess compliance with study guidelines, and to determine each 
child’s medication exposure. 
 
Bleed Data Acquisition 
1. All subjects should be instructed to go to the emergency room if there is any evidence of 
postoperative bleeding for evaluation and treatment. 


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2. As is currently standard practice at MEEI, all children with a history of bleeding, or those 
with active bleeding or evidence of an oropharyngeal clot, will be admitted, at least, for 
observation. However, this will be left to the discretion of the treating emergency room 
physician. If the child is admitted, a large bore IV will be placed and fluids administered. 
3. Children with active bleeding or a large oropharyngeal clot will return to the OR, at the 
discretion of the covering clinician, for control of hemorrhage under general anesthesia 
with endotracheal intubation. Again, however, this will be left to the discretion of the 
treating phyisician. 
4. If bleeding occurs within the first 8 postoperative days, chidren will be advised to 
discontinue the study drug, and to take tylenol 15mg/kg (maximum dose 650mg) Q4-6 
hours as needed for pain. Those children prescribed oxycodone postoperatively may 
continue to use it as well if needed. 
5. At the end of the 14 day postoperative period, or at the time of the postoperative visit, a 
study physician or participating research nurse will conduct a postoperative bleeding 
questionnaire and ask each study participants’ parents or guardian questions about any 
postoperative bleeding events. 
6. In cases where bleeding is reported, written and electronic hospital records will be 
evaluated for further information so that bleeding events can be classified according to the 
type of intervention taken. 
a. Bleeding events will be classified according to the following: 
i. Primary vs. Secondary 
1. Primary: bleed occurs < 24 hours after surgery 
2. Secondary: bleed occurs >/= 24 hours after surgery 
ii. Levels 1-3 
1. Level 1: children with any history of postoperative bleeding, 
regardless of whether there was clinical evidence of bleeding upon 
medical evaluation. This level includes all children with a history of 
postoperative bleeding who presented for evaluation/treatment by a 
physician in the Emergency Department, inpatient unit or operating 
room. 
2. Level 2: children who required inpatient admission for postoperative 
hemorrhage regardless of the need for operative intervention. This 
level of severity excludes children who were evaluated in the 
emergency room who had no clinical evidence of hemorrhage or clot 
and were deemed safe for discharge home without admission for 
observation or intervention. 
3. Level 3: the highest level of severity, includes children who required 
hospital admission and return to the operating room for control of 
post-tonsillectomy hemorrhage. 
iii. The location where the surgery took place, as well as the participating 
surgeon should be noted for each bleeding event. 
b. The DSMB must be notified of each bleeding event that is discovered in study 
subjects, as well as the total enrollment for the site at that time. 


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i. After enrollment of 100 subjects at MEEI, if the objective, type 3 bleed rate 
exceeds 6% (three times the expected average of 2% based on review of the 
literature and MEEI quality and outcomes data), the study will be put on hold 
until further evaluation has been performed. The study will be terminated if 
the type 3 bleed rate in either arm exceeds 9.3%. 
ii. On a bi-annual basis (every 6 months) after 100 patients have been enrolled, 
the data from all participating institutions will be pooled and reviewed. If the 
type 3 bleed rates exceed 6% in either study arm, the study will be 
terminated. 
iii. An interim analysis will be performed at enrollment of 102 patients. If type 3 
bleeding in the ibuprofen group is 3% above the acetaminophen group, with 
p<0.000001, or if the type 3 bleed rate exceeds 6% (> 7 bleeds), the study 
will be terminated. 
iv. Another interim analysis will be performed at the half-way point, after 
enrollment of the 362nd subject. If type 3 bleeding in the ibuprofen group is 
3% above the aceteminophen group, with p< 0.001525, the study will be 
terminated. The study will also be terminated if bleeds occur in > 22 patients 
(type 3 bleed rate > 6%). 
 
G. Data Analysis 
1. At the completion of enrollment, 722 participants, the study will be terminated and data 
reviewed using both univariate and multivariate analysis. 
a. A simple, uni-variate analysis will be performed to evaluate the association between 
ibuprofen and bleeding (we are primarily interested in evaluating the association 
between ibuprofen and type 3 bleeding). 
i. The null hypothesis (ibuprofen does not increase the risk of type 3 postoperative 
hemorrhage) will be rejected if there is a greater than 3% increase, which is the 
preset equivalence margin, in type 3 bleeding in the ibuprofen cohort in 
comparison to the acetaminophen cohort with a p value of 0.025. 
b. A multi-variate logistic regression model will be used to evaluate ibuprofen exposure, 
pain control, outcome and potential confounding factors such as narcotics use, age, 
surgical indication, gender, and operating surgeon. 
 
 
7.4 Standard of Care Procedures 
• Pregnancy testing using urine beta-HCG assays will be performed on all female participants over 
the age of 13, or those less than 13 years of age who are menstruating. Subjects will not be 
randomized into treatment groups until the results of this testing are obtained. All subjects 
found to be pregnant will be excluded from the study. 
• All patients will be administered 15mg/kg (max dose 650mg) of acetaminophen preoperatively 
prior to arrival in the preoperative area and dexamethasone 0.5mg/kg IV (maximum dose of 


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8mg) or methylprednisolone (SoluMedrol) 2.5mg/kg IV (maximum dose of 40mg) in the 
operating room prior to surgical commencement, which is standard practice at MEEI. 
• The standard method of tonsillectomy among participating surgeons will be extracapsular 
monopolar electrocautery with standard settings of 12 watts (fulgurate) using a spatula tip. 
Bleeding will be controlled with suction cautery on a setting of 12-18 watts (fulgurate). 
• Adenoidectomy will be performed at 30 watts (fulgurate). 
• Anesthetic technique, perioperative analgesia with narcotics, and post-operative care will 
remain equivalent between the two study arms. 
• Antibiotics will not be administered in the perioperative period. 
• Postoperative anti-emetic therapy will be standardized by all collaborating physicians using 
standardized order sets. 
• All patients will be prescribed postoperative analgesia, and those eligible to receive narcotics 
will also be prescribed oxycodone elixir. Postoperative hemorrhage will be managed the same, 
regardless of study participation. 
 
7.5 Follow-up Procedures (Incorporate only if follow-up procedures will be performed) 
After the 14 day study period, a postoperative questionnaire will be administered to ask about 
bleeding events and use of acetaminphen or ibuprofen during the study period. Postoperative 
study medication dosing and pain questionnaires will be collected. Any remaining study 
medication will be collected and the volume of remaining medication recorded. 
 
7.6 Unscheduled Visits 
At the end of the 14 day study period, the patient’s chart will be reviewed. Any unscheduled 
visits, Emergency Room visits or phone calls will be noted. If the child had a bleeding event, 
whenever available, hospital records will be reviewed to document the extent of bleeding and 
intervention taken. 
7.7 Early Termination 
Patients who are removed from the study due to noncompliance, intolerance of the study 
medication, or any other reason will be recorded. 
7.8 Schedule of Activities (Study Table) 


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8. SAFETY AND EFFECTIVENESS ASSESSMENTS 
 
 
8.1 Safety Assessments 
• Not applicable. Ibuprofen at 10mg/kg and Acetaminophen 15mg/kg are drugs commonly used 
in children ages 2-18 and have been shown to be effective analgesics after tonsillectomy. Urine 
beta-HCG testing will be performed per MEEI protocol to ensure female participants are not 
pregnant prior to study drug administration. 
• Should a patient inadvertently receive ibuprofen or acetaminophen in addition to the study 
drug during the study period, they will undergo liver function test or BUN, creatinine testing to 
monitor liver and kidney function. 
8.2 Effectiveness Assessments 
• At the end of the 14 day postoperative period, study questionnaires will be collected and a 
postoperative bleeding questionnaire conducted. 


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9. ADVERSE EVENT RECORDING AND REPORTING 
 
 
Definition: Please refer to the HSC’s Policy on “Reporting Adverse Events and Unanticipated Problems” 
for definitions used by the Human Studies Committee. If your definitions of adverse events is different, 
please define here. 
 
9.1 Recording Requirements 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) or device(s) will 
be recorded in the subjects’ case histories (source data, case report form). For all adverse 
events, sufficient information will be pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the event (i.e., whether the event should be classified as a 
serious adverse event) and; 2) an assessment of the casual relationship between the adverse 
event and the study drug(s) or device(s). 
Adverse events or abnormal test findings felt to be associated with the study drug(s) or 
device(s) will be followed until the event (or its sequel) or the abnormal test finding resolves or 
stabilizes at a level acceptable to the Sponsor-Investigator. 
 
➢ 
ABNORMAL TEST FINDINGS 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria 
are met: 
o The test finding is accompanied by clinical symptoms 
o The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy 
o Note: simply repeating a test finding, in the absence of any of the other listed 
criteria, does not constitute an adverse event. 
o The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study 
o The test finding is considered an adverse event by the Sponsor-Investigator of the 
IND or IDE application 
 
➢ 
CASUALTY AND SEVERITY ASSESMENT 
The Sponsor-Investigator of the IND or IDE application will promptly review documented adverse 
events and abnormal test findings to determine 1) if the abnormal test finding should be classified as 
an adverse event; 2) if there is a reasonable possibility that the adverse event was caused by the study 
drug(s); and 3) if the adverse event meets the criteria for a serious adverse event. 


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If the Sponsor-Investigator’s final determination of causality is “unknown and of questionable 
relationship to the study drug(s)”, the adverse event will be classified as associated with the use of the 
study drug(s) for reporting purposes. If the Sponsor-Investigator’s final determination of causality is 
“unknown but not related to the study drug(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history (source data or case report 
form). 
 
9.2 REPORTING PROCEDURES 
➢ 
REPORTING OF ADVERSE EVENTS TO FDA 
o The drugs used in this study are FDA approved, and this study is not part of an FDA trial. 
➢ 
 Reporting Adverse Events to Other External Entities 
o Adverse Events will be reported to the IRB of the participating institution, as well as 
investigators at other study sites. 
➢ 
Reporting Adverse Events to the  Human  Studies  Committee  (Please  follow  
HSC Policy “REPORTING ADVERSE EVENTS AND UNANTICIPATED PROBLEMS”) 
 
9.3 Withdrawal of Subjects due to Adverse Events 
• Study subjects are instructed to discontinue the study drug and switch to acetaminophen 
15mg/kg (max dose 650mg) by mouth every 4-6 hours as needed for pain should a bleeding 
event occur. The patient may continue oxycodone elixir if they were prescribed this medication 
for breakthrough pain postoperatively. 
o Should a bleeding event occur, it will be classified as primary or secondary, and by 
severity (type 1, type 2, or type 3). Guidelines for these classifications are outlined in 
section 7.3 of this document. 
o Patients who experience a bleeding event will still come to their follow-up appointment, 
which is scheduled at the time their surgery was booked. 
• Study subjects will be withdrawn from the study if they receive acetaminophen or ibuprofen 
during the study period, if they self-discontinue the study medication, or if the medication was 
stopped and they were started on a different medication for postoperative analgesia. 
• Subjects removed from the study will remain in the analysis using an intention to treat model. 


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10. STATISTICAL METHODS/DATA ANALYIS 
 
 
10.1 Primary endpoint(s) or outcome measure(s) 
 
1. Pain control Data Acquisition 
• Patients and their family members will receive a packet of 9 study medication dosing pain 
control questionnaires (see Appendix B) along with the study drug, and will be instructed to 
fill out this questionnaire at the end of each postoperative day (9 days total, postoperative 
day 0-8). See Appendix B. 
• Study subjects and their parents will be asked to bring these questionnaires to their first 
postoperative visit for collection. 
• Study subjects will also be asked to bring the bottle of any remaining study medication. This 
will allow study personnel to assess compliance with study guidelines, and to determine 
each child’s medication exposure. 
2. Bleed Data Acquisition 
1. All subjects should be instructed to go to the emergency room if there is any evidence of 
postoperative bleeding for evaluation and treatment. 
2. As is currently standard practice at MEEI, all children with a history of bleeding, or those 
with active bleeding or evidence of an oropharyngeal clot, will be admitted, at least, for 
observation. However, this will be left to the discretion of the treating emergency room 
physician. If the child is admitted, a large bore IV will be placed and fluids administered. 
3. Children with active bleeding or a large oropharyngeal clot will return to the OR, at the 
discretion of the covering clinician, for control of hemorrhage under general anesthesia 
with endotracheal intubation. Again, however, this will be left to the discretion of the 
treating phyisician. 
4. If bleeding occurs within the first 8 postoperative days, chidren will be advised to 
discontinue the study drug, and to take tylenol 15mg/kg (maximum dose 650mg) Q4-6 
hours as needed for pain. Those children prescribed oxycodone postoperatively may 
continue to use it as well if needed. 
5. At the end of the 14 day postoperative period, or at the time of the postoperative visit, a 
study physician or participating research nurse will conduct a postoperative bleeding 
questionnaire and ask each study participants’ parents or guardian questions about any 
postoperative bleeding events. 
6. In cases where bleeding is reported, written and electronic hospital records will be 
evaluated for further information so that bleeding events can be classified according to the 
type of intervention taken. 
a. Bleeding events will be classified according to the following: 
i. Primary vs. Secondary 
1. Primary: bleed occurs < 24 hours after surgery 
2. Secondary: bleed occurs >/= 24 hours after surgery 


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ii. Levels 1-3 
1. Level 1: children with any history of postoperative bleeding, 
regardless of whether there was clinical evidence of bleeding upon 
medical evaluation. This level includes all children with a history of 
postoperative bleeding who presented for evaluation/treatment by a 
physician in the Emergency Department, inpatient unit or operating 
room. 
2. Level 2: children who required inpatient admission for postoperative 
hemorrhage regardless of the need for operative intervention. This 
level of severity excludes children who were evaluated in the 
emergency room who had no clinical evidence of hemorrhage or clot 
and were deemed safe for discharge home without admission for 
observation or intervention. 
3. Level 3: the highest level of severity, includes children who required 
hospital admission and return to the operating room for control of 
post-tonsillectomy hemorrhage. 
iii. The location where the surgery took place, as well as the participating 
surgeon should be noted for each bleeding event. 
 
10.2 Secondary endpoints or outcome measure(s) 
• We will look at bleeding and pain data and its relationship to the age and gender of the study 
subject, participating institutuion, surgeon, and indication for surgery. 
 
10.3 Sample Size Determination 
In order to determine our sample size, we looked at data collected at our institution 
(MEEI) during a previous study investigating post-tonsillectomy bleeding when steroids were 
given intraoperatively (Dr. Gallagher and Dr. Hartnick’s study of the use of dexamethasone and 
the risk of postoperative bleeding, in press awaiting JAMA publication). In this cohort, 137 
children received dexamethasone and postoperative acetaminophen, and there were 3 type 3 
bleeds requiring return to the operating room for control of hemorrhage, giving a roughly 2% 
type 3 bleed rate. This is consistent with MEEI quality and outcomes data for 2005-2009, which 
demonstrated that 2.25% (SD 0.5) of tonsillectomies performed during this period required 
return to the operating room (type 3 bleeding) for control of hemorrhage. Therefore, we used 
a type 3 bleed rate of 2% as our predicted type 3 bleed rate for patients in the control, 
acetaminophen arm. 
From literature review of prospective trials, meta-analyses and retrospective reviews, the 
average NSAID bleed rate is 10.9%, representing roughly a 6% increase in bleed rate. Previous 
studies designed to evaluate bleeding rates as a primary outcome measure were powered to 
only detect a significance between treatment groups if bleed rates differed by >20%. Based on 
consensus judgment among the PI, AI and key personnel with review of the literature, it was 
agreed that the potential benefits conferred by ibuprofen would be acceptable provided the 


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administration was associated with no more than a 3% absolute increase in bleeds requiring 
operative intervention compared to the standard treatment of acetaminophen. 
Dr. Rie Maurer then calculated a projected sample size using a group sequential two 
proportions non-inferiority method using East v 5.4.2 and O’Brien-Flemming stopping 
boundaries determined by means of the Lan-DeMets approach with the following parameters: 
an alpha of 0.025, power of 80%, 5% projected lost to follow-up rate, acetaminophen (control) 
type 3 bleed rate of 2%, noninferiority diference of 3%, and 3 anticipated unblinded looks at the 
data. Using these parameters, the following sample sizes were calculated: 
 
 
One sided alpha 
Power 
Proportion of 
bleeding in 
Acetaminophen 
group 
Non inferiority 
Difference 
Sample size 
0.025 
80% 
2% 
3% 
343 per group, 686 total 
(361 per group,722 total with 
loss of Fu 5%) 
 
 
 
Look 
Accumulated info 
Accumulated Sample 
Size 
Z value 
boundary 
Cum. Alpha spent 
 
1 
14% 
48 per group; 96 total 
(51 per group 102 total 
with loss of Fu 5%) 
5.877 
<0.000001 
 
2 
50% 
172 per group; 344 total 
(181 per group; 362 total 
with loss of Fu 5%) 
2.963 
0.001525 
 
3 (final) 
100% 
343 per group; 686 total 
(361 per group; 722 total 
with loss of Fu 5%) 
1.969 
0.025 
 
 
 
10.4 Analysis Population (if applicable) 
• We plan to use an intention to treat method when we unblind and analyze our data. 


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10.5 Effectiveness Analysis (if applicable) 
We plan to initially analyze the crude association between ibuprofen and bleeding rate using 
simple, univariate analysis. We will then construct a multivariate logistic regression model 
including ibuprofen exposure, pain control, outcome, and potential confounding factors such as 
age, surgical indication, gender, and operating surgeon. Analysis will be performed using an 
intention to treat analysis. Impact of losses to follow-up will be assessed using sensitivity 
analysis. Statistical analysis and data management will be performed using STATA, SAS and 
Microsoft Excel. 
Interval looks at the data are planned. If, after enrollment of 100 children at MEEI, then on a bi- 
annual basis, if the type 3 bleed rate does not exceed 9.3%, the study will continue recruitment 
until n= 102. At that time, a first look of the data will be planned. If the bleed rate in the 
ibuprofen exceeds 3% that in the acetaminophen group with a p<0.000001, recruitment will be 
terminated. If not, as long as type 3 bleed rate remains < 6%, recruitment will continue until 
n=362. At that time, a second unblinded look at the data is planned.  If the noninferiority 
margin exceeds 3% with a p<0.001525, the study will be terminated.  If not and the type 3 
bleed rate remains < 6%, the study will continue until we reach a total n= 722. If the ibuprofen 
group bleeding rate exceeds 3% with a p<0.025 at that time, ibuprofen will be considered 
inferior to the control, acetaminophen group. 
Please note that this statistical plan deviates from the original plan outlined in the MEEI 
protocol approved on 5.2.12. When an acetaminophen control group type 3 bleed rate 
became available, we felt it was important to use this in our sample size calculations. In 
previous literature reviews. Type 3 bleed rates were not available, and previous control group 
bleed rates were based on all types of bleeding. Additionally, because we planned to perform 
a look at the bleed rate after enrollment of 100 participants as part of our initial safety 
analysis, we felt it would be appropriate to perform an unblinded look at the data at that 
time, for patient safety, and to account for this in our sample size calculations. 
 
10.6 Safety Analysis 
Interval looks at the data are planned. If, after enrollment of 100 children at MEEI, then on a bi- 
annual basis, if the objective, type 3 bleed rate does not exceed 9.3%, the study will continue 
recruitment until n= 102. At that time, a first look of the data will be planned. If the bleed rate 
in the ibuprofen exceeds 3% that in the acetaminophen group with a p<0.000001, recruitment 
will be terminated. If not, as long as the type 3 bleed rate remains < 6%, recruitment will 
continue until n=362. At that time, a second unblinded look at the data is planned. If the 
noninferiority margin exceeds 3% with a p<0.001525, the study will be terminated. If not and 
the type 3 bleed rate remains < 6%, the study will continue until we reach a total n= 722. If the 
ibuprofen group bleeding rate exceeds 3% with a p<0.025 at that time, ibuprofen will be 
considered inferior to the control, acetaminophen group. 


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10.7 Interim Analysis 
Interval looks at the data are planned. If, after enrollment of 100 children at MEEI, then on a bi- 
annual basis, if the type 3 bleed rate does not exceed 9.3%, the study will continue recruitment 
unless otherwise instructed after DSMB review. We will plan to perform a first look at the data 
at n= 102.  If the bleed rate in the ibuprofen exceeds 3% that in the acetaminophen group with 
a p<0.000001, recruitment will be terminated. If not, as long as type 3 bleed rate remains < 6%, 
recruitment will continue with permission of our DSMB until n=362. At that time, a second 
unblinded look at the data is planned. If the noninferiority margin exceeds 3% with a 
p<0.001525, the study will be terminated. If not and the type 3 bleed rate remains < 6%, the 
study will continue with permission of the DSMB until we reach a total n= 722. If the ibuprofen 
group bleeding rate exceeds 3% with a p<0.025 at that time, ibuprofen will be considered 
inferior to the control, acetaminophen group. 
 
 
 
10.8 Data and Safety Monitoring 
• The DSMB at MEEI is comprised for Dr. Stacey Gray, Dr. Maynard Hansen, and Dr. Mark Volk. 
• Each time a bleeding event occurs, the institution’s DSMB and investigators at all participating 
institutions will be notified with a summary of the event (primary or secondary bleed, type of 
bleeding (type 1, 2 or 3) and circumstances surrounding the bleed. The DSMB will be notified 
regarding the total enrollment and overall bleed rate at that time. 
o If type 3 bleeding rates exceed 6% after enrollment of at least 100 subjects at MEEI 
(three times the expected rate of 2% based on review of the literature and MEEI quality 
and outcomes data), the study will be put on hold at all sites pending further 
investigation. If the type 3 bleed rate exceeds 6% in either study arm, the study will be 
terminated 
o On a bi-annual basis (every 6 months) after at least 100 patients have been enrolled, the 
data from all participating institutions will be pooled and reviewed. If type 3 bleed rates 
exceed 6%, the study will be unblinded. If type 3 bleeding exceeds > 6% in either study 
arm, the study will be terminated. 
 
o The DSMB will evaluate data from each of the 3 looks of the data. During the first two 
looks, the DSMB will determine if the study should continue. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
12. DATA HANDLING AND RECORD-KEEPING 
 
 
12.1 Data Recording and Record-Keeping 
Each subject will have an entry in an electronic spreadsheet, maintained in a password Microsoft Excel 
Document available only to investigators with the study. Source data describes the clinical findings, 
observations, and other information contained in the patient’s electronic and hospital records, 
pharmacy dispensing records. Pertinent source data for each subject will be entered into their entry 
on the spreadsheet. 
The electronic data recording data system being used for this clinical research study has not been fully 
certified as being compliant with the FDA regulations at 21 CFR Part 11 due to the limited scope of this 
clinical research study. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
14. STUDY DISCONTINUATION CRITERIA 
 
 
14.1 Discontinuation of Individual Research Subjects 
• See conditions under Section 5.2 
14.2 Sponsor-Investigator Discontinuation of the Clinical Research Study 
• There is no study related sponsor. 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
15. APPENDICES 
 
 
15.1 Schedule of Events 
 
 
 
Activity 
Screening 
Date of surgery 
(Postoperative 
day 0) 
Postoperative 
days 1-8 
Postoperative day 
9 
Bleeding Event 
End of 14-day 
postoperative 
period/follow-up visit 
Informed consent 
X 
X 
Inclusion/Exclusion Criteria 
X 
Urine beta-HCG testing for 
female patients who meet 
screening criteria (standard 
preop practice at MEEI) 
X 
X 
Randomization 
X 
Pharmacy prepares and 
dispenses bottle with 36 doses 
of study medication 
X 
Dosing and pain questionnaires 
distributed 
X 
Postoperative instructions 
distributed 
X 
Dosing and pain questionnaires 
filled out 
X 
X 
Stop Study Medication 
X 
X 
Start acetaminophen 15mg/kg 
po Q4-6 hours prn pain 
X 
X 
Physician exam/evaluation 
X 
X 
Collect remaining study 
medication 
X 
Collected completed dosing and 
pain questionnaires 
X 
Administer bleeding 
questionnaire 
X 
Monitor for adverse events 
X 
X 
X 
X 
X 
Monitor compliance 
X 
X 


Massachusetts Eye and Ear Infirmary 
SUPP M - Clinical Trial Template 
 
 
 
15.2 Case Report Form(s) 
Case report forms are not being used for this study. The latest version of our excel spreadsheet for 
recording data was approved by the MEEI IRB on 5/1/1. 

SAP_000.pdf: 
 
 
Postoperative Ibuprofen and the Risk of 
Bleeding after Tonsillectomy with or without 
Adenoidectomy 
 
Analysis Plan 
 
 
Prepared by: 
Gillian Diercks, M.D. 
Rie Maurer, M.S. 
 
May 1, 2012 
 
 


Introduction 
 
This document summarizes the statistical analysis plan for the study entitled 
“Postoperative Ibuprofen and the Risk of Bleeding after Tonsillectomy with or without 
Adenoidectomy”.   
 
Study design 
 
This study is a randomized, two-arm, blinded, non-inferiority study to evaluate the 
effects of ibuprofen on postoperative bleeding and pain.  Consented and eligible 
subjects will be randomized to receive either ibuprofen (treatment arm) or 
acetaminophen (control arm) postoperatively.  Eligible subjects are children aged 2-18 
years undergoing tonsillectomy with or without adenoidectomy with electrocautery for 
recurrent tonsillitis and sleep disordered breathing/obstructive sleep apnea (OSA).  
Children with the following characteristics will be excluded from participation in the 
study: NSAID or aspirin allergy, acetaminophen allergy, bleeding disorders, asthma, 
lung, kidney or liver disease, or allergy to the dyes used in the medications.   
 
The primary objective of this study is to determine if postoperative ibuprofen at 10mg/kg 
dosing QID (for times daily, roughly Q6 hours) postoperatively for 9 days is associated 
with an increased rate of post-tonsillectomy bleeding requiring operative intervention for 
hemostasis (type 3 bleeding) in children when compared with acetaminophen at 
15mg/kg dosing QID.  Secondary outcomes include comparing rates of post-
tonsillectomy hemorrhage based on patient age, indication for tonsillectomy, and 
operating surgeon, as well as evaluating the effectiveness of ibuprofen as a post-
tonsillectomy analgesic.   
 
This is a non-inferiority study which seeks to demonstrate that post-operative ibuprofen 
is not associated with a clinically significant increase in postoperative bleeding rate, 
compared with acetaminophen, in children undergoing tonsillectomy.  The null 
hypothesis for the primary aim is inferiority of ibuprofen; that is, subjects randomized to 
receive ibuprofen postoperatively after tonsillectomy will have an increased rate of post-
tonsillectomy hemorrhage requiring operative intervention (type 3 bleeding) compared 
with subjects receiving acetaminophen.  The alternative hypothesis is that bleeding rate 
with ibuprofen is not greater than acetaminophen by more than the non-inferiority 
margin.  This non-inferiority margin was set at 3%.  
 
The overall sample size of 722 (361 per study arm) for the primary analysis was 
calculated using a group sequential two proportions non-inferiority method using East 
V5.4.2 and O’Brien –Flemming stopping boundaries determined by means of the Lan-
DeMets approach with the following parameters: one sided alpha of 0.025, power of 
80%, 5% projected loss to follow-up rate, acetaminophen (control) type 3 bleed rate of 


2%, non-inferiority  difference of 3%, and 3 anticipated looks at the data (14%, 50% and 
100% enrollment). 
 
Subjects will be recruited from the following five sites: 
1. Massachusetts Eye and Ear Infirmary (MEEI), Boston, MA 
2. Madigan Army Base, Tacoma, WA 
3. Naval Medical Center, San Diego, CA 
4. Naval Medical Center, Portsmouth, VA 
 
Recruited subjects that are eligible will be offered to consent and randomized in a one-
to-one scheme using a uniform (1, 2) random number generator (www.randomizer.org) 
in blocks.  This is a double-blinded study.  Both the patient/parent and the healthcare 
providers (surgeon and nurses) will be blinded to which arm the patient is randomized.   
 
The surgical technique used in the tonsillectomy with or without adenoidectomy along 
with the pain management prior and during the surgery is prescribed by the protocol.  
Postoperative pain management is dependent on randomization.  All subjects will be 
randomized prior to surgery.  
 
Main Outcome Measure and Classification of Bleeding Events 
 
Post-tonsillectomy bleeding is the main outcome measure.  This is categorized into type 
1, type 2, and type 3 bleeding based on severity as well as time of bleeding, as 
determined by a physician-conducted postoperative bleeding questionnaire and review 
of written and electronic hospital records.  These events will have two classifications: 
1. Primary vs. Secondary (based on timing) 
a. Primary: bleed occurs < 24 hours after surgery 
b. Secondary: bleed occurs >/= 24 hours after surgery 
2. Levels 1-3 (based on severity) 
a. Level 1: children with any history of postoperative bleeding, regardless of 
whether there was clinical evidence of bleeding upon medical evaluation.  
This level includes all children with a history of postoperative bleeding who 
presented for evaluation/treatment by a physician in the Emergency 
Department, inpatient unit or operating room. 
b. Level 2: children who require inpatient admission for postoperative 
hemorrhage regardless of the need for operative intervention.  This level 
of severity excludes children who were evaluated in the emergency room 
who had no clinical evidence of hemorrhage or clot and were deemed safe 
for discharge home without admission for observation or intervention. 
c. Level 3: the highest level of severity, includes children who required 
hospital admission and return to the operating room for control of post-
tonsillectomy hemorrhage.  This is our main outcome measure. 
 


The endpoint for the primary analysis is either 1.a. or 1.b. and only 2.c. above (i.e. all 
Level 3 primary or secondary tonsil bleeds).  For those subjects with more than one 
distinct bleed event within the study follow-up period, the most severe event will be 
considered for the primary analysis. 
 
Secondary Endpoint: Effectiveness 
 
Effectiveness will be measured by self-reported pain control.  See Appendix I for pain 
questionnaire (only the questionnaire from Day 0 is included as Days 1-8 are the same).  
The primary definition of effectiveness will be overall rating of the child’s pain (mild, 
moderate, severe); secondary definitions will include the four categories for crying, 
excitement, anxiety and verbalization of pain (0, 1, 2; corresponding to no experience of 
this symptom, mild and moderate/severe). 
 
Specific Aims 
 
• Primary Aim 1: To compare the rates of post-tonsillectomy bleeding between 
pediatric patients who receive postoperative ibuprofen to those who receive 
acetaminophen in a prospective, randomized, blinded and controlled trial. 
• Secondary Aim 2: To compare the rates of post-tonsillectomy hemorrhage when 
studying different groups of patients based upon their age, indication for 
tonsillectomy, or operating surgeon. 
• Secondary Aim 3: To evaluate effectiveness of ibuprofen as a post-
tonsillectomy analgesic in comparison to acetaminophen, which is currently the 
standard of care at our institution. 
 
Statistical summaries and methods 
 
All summaries and analyses will be presented overall and by study arm.  There are two 
study arms: ibuprofen and acetaminophen. 
 
Screening and eligibility 
 
• Total # screened and reasons for ineligibility or reasons for refusal of consent 
(based on available data) will be presented in a CONSORT figure, along with 
some of the data in the sections that follow.  A template for this figure from 
http://www.consort-statement.org/ is available in Appendix II. 
 
Accrual 
 
• Table: Randomization of subjects by month (or quarter?) by clinical center.  
Dates of first and last randomization. 


• Figure: Either just a plot of # randomized on the y-axis and month+year on the x-
axis OR a comparison of observed randomization with targeted randomization 
• Describe any eligibility criteria violations.  For example, a subject was 
randomized but consent was not in place or found to not meet a particular 
eligibility criterion after being randomized.  Describe how these subjects were 
handled. 
• Table: Number of subjects randomized by study arm by month+year and 
separately by clinical site. 
 
Baseline characteristics and demographics 
 
Baseline is defined as the last available value obtained on or before the day of 
randomization.   
 
Table: summarize the following variables by study arm: (“Continuous statistics” will 
present: mean, standard deviation (SD), median, 10th and 90th percentiles, minimum 
and maximum values): 
• Sex: number (%) by sex 
• Age: continuous statistics 
• Indication for surgery: number (%) by recurrent tonsillitis, sleep disordered 
breathing, adenotonsillar hypertrophy, or other 
• Surgery type: number (%) by tonsillectomy or tonsillectomy with adenoidectomy 
• Surgeon performing operation: number (%) by surgeon number 
• Study site: number (%) by the four sites 
• Supplementary procedures: number (%) by procedure 
• Prescribed narcotics postoperatively: number (%) prescribed 
 
Completeness of Follow-up 
 
Table: Number (%) by the following categories: 
• Completed protocol-specified period of follow-up through 14 days postoperative 
• Failure to complete follow-up, with reasons for loss to follow-up 
 
Status of randomized treatment (ibuprofen/acetaminophen) 
 
Table: Number (%) by the following categories: 
• Completed assigned study treatment as prescribed by the protocol (with no 
missed doses) 
• Completed assigned study treatment but missed some doses or temporary 
treatment interruptions (separate adherence issues from toxicity issues and 
summarize number of missed doses and reasons missed) 


• Early discontinuation of study treatment (including reasons for premature 
discontinuation, including toxicity) 
 
Adverse events (other than bleeding) 
 
Table: Hematological abnormalities by test code and grade separately by study arm 
(only include events that are at least one grade higher than existing graded event at 
baseline) 
Table: Diagnosis by category (as determined by principal investigator upon review of 
recorded diagnoses) and grade separately by study arm (only include events that are 
new or one grade higher than those existing at baseline) 
 
Primary Objective 
 
The primary analysis will be intent-to-treat (ITT).  All randomized subjects will be 
included with the exception of any that withdrew consent or were found to be ineligible 
post-randomization (see Study Design section above) and did not receive the study 
medication.  All other randomized subjects will be included. 
 
This ITT primary analysis (Aim 1) will be a simple, univariable analysis to evaluate the 
association between ibuprofen and bleeding.  As described above, the outcome will be 
type 3 bleeding (including both primary and secondary).  The null hypothesis (the type 3 
postoperative hemorrhage rate in subjects on the ibuprofen arm differed from the 
bleeding rate of subjects on the acetaminophen arm) will be rejected if the difference in 
bleeding rates do not exceed 3%, which is the preset non-inferiority margin, and the 
conclusion will be that the type 3 bleeding in the ibuprofen study arm is not greater than 
that in the acetaminophen arm by more than 3%.  Thus, the hypotheses are as follows: 
 
𝐻0: 𝑝𝑖𝑏𝑢𝑝𝑟𝑜𝑓𝑒𝑛− 𝑝𝑎𝑐𝑒𝑡𝑎𝑚𝑖𝑛𝑜𝑝ℎ𝑒𝑛 ≥0.03 
𝐻𝑎: 𝑝𝑖𝑏𝑢𝑝𝑟𝑜𝑓𝑒𝑛− 𝑝𝑎𝑐𝑒𝑡𝑎𝑚𝑖𝑛𝑜𝑝ℎ𝑒𝑛< 0.03 
 
One-sided confidence intervals will be used to compare the difference in bleeding rate 
between the two study arms.  This difference will be compared using a Wald test with 
an overall significance level of 0.025.  Analysis will be performed for both primary and 
secondary bleeding. 
 
Secondary Objectives 
 
Secondarily, a multivariable logistic regression model (Aim 2) will assess this primary 
bleeding outcome with adjustment for pain control (primary definition of effectiveness as 
recorded on the day before the bleed event) and potential confounding variables 
(including study site, narcotics use, age, surgical indication, gender and operating 


surgeon).  A variable will be considered confounding with study arm if the parameter 
estimate for study arm changes by more than 10% once the potential confounder is 
included in the model.  Any variables meeting this definition will be included in the 
adjusted model regardless of significance-level. 
 
Both the univariable and multivariable analyses will include all randomized subjects and 
be intent-to-treat.  This includes those that are lost to follow-up.  Those that are lost to 
follow-up will be assumed to not have had a Type 3 bleed unless there is a hospital 
record of type 3 bleeding on chart review.  Subjects considered to be lost to follow-up 
will be those who do not return for their postoperative visit.   
 
The final protocol-specified secondary objective (Aim 3) is to evaluate the effectiveness 
of ibuprofen as a post-tonsillectomy analgesic in comparison to acetaminophen.  Using 
the primary definition of effectiveness we will compare the experience of pain based on 
the overall category (mild, moderate or severe) and study treatment arm (mortrin versus 
acetaminophen) using ordinal logistic regression separately for each postoperative day.  
Subsequent regression models will be adjusted for study site, narcotics use, age, 
surgical indication, gender and operating surgeon.  It is not of interest to assess 
changes in pain over time since post-tonsillectomy pain does not improve consistently in 
the first eight days post-surgery.  For example, it is not unusual for a patient to have 
severe pain on postoperative (PO) days 0-3, improved pain levels on PO days 3-5 and 
then increased pain on PO days 5-8.  
 
Additionally, assess the correspondence between the primary definition of effectiveness 
and the secondary definitions (crying, excitement, anxiety and verbalization of pain).  
Tables will summarize overall primary pain response by the each of the four secondary 
definitions, separately for each of the 9 days that this data was collected.  The Mantel-
Haenszel test will be used to assess whether the primary and secondary definitions 
increase or decrease in similar ways (since are measures of pain are ordinal and we are 
interested in the linear association between these two measures). 
 
 


Appendix I: Medication Dosing Schedule and Pain Scale Questionnaire 
 
 
Patient Name: ____________________________________________________ 
 
 
Date of Surgery: __________________________________________________ 
 
 
 
MEDICATION DOSING AND PAIN SCALE INSTRUCTIONS 
 
 
As part of your participation in our study investigating the use of ibuprofen after tonsillectomy, please 
complete the following pain scale daily each evening.  This packet contains 9 scales.  The first should be 
completed today- the date of surgery- and the other scales should be completed on postoperative day 1 
through 8, for a total of 9 days.     
 
If your child was also prescribed oxycodone and received that medication, please indicate this on the 
questionnaire corresponding to the day during which it was given. 
 
Please bring your completed questionnaires, as well as any remaining study medication, to your 
postoperative visit for collection and review. 
 
 
 


Patient Name: ____________________________________________________ 
 
POSTOPERATIVE DAY 0 (DAY OF SURGERY) MEDICATION DOSING AND PAIN SCALE 
 
Please place a check in the appropriate box each time you give your child a dose of 
the study medication. 
 
 
DOSE 1 
DOSE 2 
DOSE 3 
DOSE 4 
Check the box if 
medication was 
given 
 
 
 
 
 
If your child is eligible to receive oxycodone, was this given today? (circle response) 
Yes 
 
 
 
No 
 
Directions: For each item, please circle the number that best corresponds to your 
child’s behavior. 
 
Crying? 
No 
0 
Yes but response to TLC* 
1 
Yes but does not respond to 
TLC* 
2 
 
 
 
Excitement 
None 
0 
Restless 
1 
Thrashing 
2 
 
 
 
Anxiety 
Asleep 
0 
Mild 
1 
Hysterical  
2 
 
 
 
Verbalization of pain 
Asleep/states no pain 
0 
Cannot localize pain 
1 
Can localize pain 
2 
* TLC = tender loving care 
 
Directions: Please rate your child’s pain as mild, moderate, or severe based on the 
descriptions noted below. 
 
Rate your child’s pain: 
 
Able to tolerate soft diet, slept for 8-10 hours per night 
Mild 
Difficulty tolerating a soft diet, awoke once or twice in 8-10 
hour night complaining of pain 
Moderate 
Could not tolerate a soft diet, tolerates liquid diet at best; 
awoke several times over 8-10 hour night because of pain 
and discomfort 
Severe 
 
 
 


Appendix II 
 
 
CONSORT 2010 Flow Diagram 
 
Assessed for eligibility (n=  ) 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
   Other reasons (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Randomized (n=  ) 
Enrollment