The Use of Ketorolac in Surgical Neonates
Phase: PHASE2
Conditions: Postoperative Pain Control in Surgical Neonates
Sponsor: Nationwide Children's Hospital

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The Safety of Ketorolac in Surgical Neonates  
IND Number:  In progress 
Principal Investigator: Jennifer H. Aldrink, MD 
 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH regulations 
• 
Institutional and IRB policies and guidelines 
• 
Terms of Award 
 
All key personnel (all individuals responsible for the design and conduct of this study) have completed 
Human Subjects Protection Training. 
 

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TABLE OF CONTENTS 
Statement of Complicance………………………………………………….…………………………..i 
Table of Contents………………………………………………………………………………………ii-iii 
List of Abbreviations…………………………………………………………….………..……………iv-v 
Protocol Summary………………………………………………………………………………………vi 
Schematic of Study Design…………………………………………………………………………….vii 
1 
Key Roles……………………………………………………………………………………….1 
2 
Background Information and Scientific Rationale………………………………………..…2 
2.1 Background Information……………………………………………………………..……2 
2.2 Rationale………………………………………………………………………..………….3 
2.3 Potential Risks and Benefits……………………………………………………..………3 
 
2.3.1 Potential Risks…………………………………………………………..……...3 
 
2.3.2 Known Potential Benefits………………………………………..…………….3 
    3  
Objectives…………………………………………….……………………….………………..4 
 
3.1 Study Objectives………………………………………………………………………..…4 
 
3.2 Study Outcome Measures……………………………………………………………..…4 
 
 
3.2.1 Primary Outcome Measures…………………………………..………………4 
 
 
3.2.2 Secondary Outcome Measures………………………………………..……...4 
   4  
Study Design…………………………………………………………….………….………….5 
   5 
Study Enrollment and Withdrawal……………………………………………………………6 
 
5.1 Subject Inclusion Criteria…………………………………………………………………6 
 
5.2 Subject Exclusion Criteria…………………………………………………….…………..6 
 
5.3 Treatment Assignment Procedures……………………………………………….……..6 
 
 
5.3.1 Randomization Procedures………………………………………………….…7 
 
 
5.3.2 Masking Procedures……………………………………………………………7 
 
 
5.3.3 Reasons for Withdrawal……………………………………………….……….7 
 
 
5.3.4 Withdrawals………………………………………………………………….…..8 
  6 
Study Intervention/Investigational Product………………………………………….……….9 
 
6.1 Study Product Description………………………………………………………..……….9 
 
 
6.1.1 Acquisition………………………………………………………………..………9 
 
 
6.1.2 Formulation, Packaging, Labeling………………………………………….….9 
 
 
6.1.3 Product Storage and Stability………………………………….……...…….…9 
 
6.2 Dosage, Preparation, Administration……………………………………………….……9 
 
6.3 Modification of Study Intervention……………...…………………………………….….10 
 
6.4 Accountability Procedures for the Study Intervention……………………………….…10 
 
6.5 Concomitant Medications/Treatments………………………………………….………..10 
 7 Study Schedule………………………………………………………………………………….……11 
 
7.1 Study Evaluations………………………………………………………………………….11 
 
7.2 Follow-Up………………………………………………………………………………...…11 
 8 Study Procedures/Evaluations………………………………………………………………...……12 
 
8.1 Specification of Safety Parameters………………………………………………………12 

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8.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters..12 
 
 
8.2.1 Adverse Events………………………………………………………………….12 
 
 
8.2.2 Serious Adverse Events………………………………………………………..13 
 
 
8.2.3 Procedures in the Event of Abnormal Laboratory values/Clinical Findings14 
 
8.3 Reporting Procedures……………………………………………………………………..14 
 
 
8.3.1 Regulatory Reporting…………………………………………………………...14 
9 Clinical Monitoring………………………………………………………………………………….…15 
10 Statistical Considerations………………………………………………………………………..…16 
 
10.1 Study Hypothesis…………………………………………………………………………16 
 
10.2 Sample Size Considerations…………………………………………………………….16 
 11 Ethics/Protection of Human Subjects…………………………………………………………….17 
 
11.1 Ethical Standard………………………………………………………………………….17 
 
11.2 IRB…………………………………………………………………………………………17 
 
11.3 Informed Consent Process………………………………………………………………17 
 
 
11.3.1 Informed Consent/Assent…………………………………………………….17 
 
11.4 Subject Confidentiality……………………………………………………………………18 
 
11.5 Subject Discontinuation………………………………………………………………….18 
12 Data Handling and Record Keeping……………………………………………………………….19 
 
12.1 Data Management Responsibilities…………………………………………………….19 
 
12.2 Data Capture Methods…………………………………………………………………..19 
 
12.3 Types of Data……………………………………………………………………….…….19 
 
12.4 Study Records Retention………………………………………………………….…….19 
 
12.5 Protocol Deviations………………………………………………………………………19 
13 Publication Policy……………………………………………………………………………………20 
14 Literature References………………………………………………………………………….……21 
15 Supplement/Appendices……………………………………………………………………………22 
 
15.1 Table 1 Pharmacologic Management Policy…………………………………….…….27 
 
15.2 Table 2 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MedDRA Ò 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NCI 
National Cancer Institute, NIH, DHHS 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 

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PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
US 
United States 
WHO 
World Health Organization 
 
 

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PROTOCOL SUMMARY 
 
Title: 
The Safety of Ketorolac in Surgical Neonates 
Phase: 
II 
Population: 
Neonates aged 1week to 3 months who undergo an 
abdominal, cardiac, or thoracic surgical procedure at 
Nationwide Children’s Hospital, Columbus, Ohio.  Sample 
size will include 60 patients. 
Number of Sites: 
Nationwide Children’s Hospital, Columbus, Ohio 
Study Duration: 
1-2 years  
Subject Participation 
Duration: 
Five days 
Description of Agent or 
Intervention: 
Ketorolac 0.5mg/kg (or placebo, 0.9% normal saline) 
intravenous every 8 hrs for 72hrs. First dose administered 
within 24hrs following the completion of the surgical 
procedure.  
Objectives: 
 
Primary:  The primary purpose of this study is to compare bleeding 
events in neonates who receive ketorolac and those who do not 
receive ketorolac. We hypothesize that ketorolac is safe and 
effective in infants > 37wks corrected gestational age and at least 
one week of age. 
Secondary: We intend to evaluate daily creatinine levels, pain 
scores, urine output per shift, platelet counts, hemoglobin levels, 
number of days on the ventilator, amount of opioid administered, 
blood pressure, and reintubation events on all patients in this study 
as secondary study points. 
 
Description of Study 
Design: 
See schematic below 
Estimated Time to 
Complete Enrollment: 
1-2 years 

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*Schematic of Study Design: 
 
 
 
 
>37wk CGA 
>1 week of age 
Moderate to severe category 
abdominal or cardiothoracic 
surgical procedure 
Ketorolac 0.5mg/kg IV q8h – started 
within 24h of OR 
+ 
Standard pain control regimen per 
category of procedure 
 
Placebo (0.9% normal saline in 
equivalent volume) IV q8h – started 
within 24h of OR 
 
+ 
Standard pain control regimen per 
t
f
d
-Follow for 5 days for primary and 
secondary endpoints 
-Daily CBC, Chem 
-Follow for 5 days for primary and 
secondary endpoints 
 
-Daily CBC, Chem 
 

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1 
KEY ROLES 
 
Individuals: 
Principal Investigator:  Jennifer H. Aldrink, MD 
Co-Investigators: Teresa Puthoff, PharmD 
                               Joseph Tobias, MD 
 
 
 
 
Institutions: 
Nationwide Children’s Hospital 
700 Children’s Drive, Columbus Ohio 43205 
Jennifer H. Aldrink, MD 
Phone Number: 614.722.2650 
Fax Number: 614.722.2663 
E-mail:  Jennifer.aldrink@nationwidechildrens.org 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Ketorolac is a nonsteroidal anti-inflammatory agent that has been demonstrated to be an 
effective drug in relieving moderate to severe postoperative pain in adults and children.1-5 
Ketorolac can reduce the opioid requirements following surgery, and may therefore prevent 
some of the opioid-induced undesirable adverse effects, including respiratory depression, 
central nervous system disturbances, urinary retention, and prolonged ileus. However, 
ketorolac carries its own risks of increased bleeding complications and renal insufficiency. 
Ketorolac's mechanism of action is as a reversible inhibitor of cyclooxygenase-1 and -2 (COX-1 
and COX-2) enzymes, which results in the decreased formation of prostaglandin precursors. 
This has some effect on renal perfusion. In addition, given its effects on platelet adhesion and 
aggregation, it may prolong bleeding time. Ketorolac is renally cleared, and in patients with 
renal dysfunction, its clearance may be prolonged.  
 
Neonates and young infants can be particularly challenging in the postoperative setting given 
legitimate concerns of respiratory depression following opioid administration.1 However, 
minimal safety or efficacy data on ketorolac currently exists in this age group in whom this 
drug could be a potentially useful adjuvant to opioids. The purpose of this study is to 
characterize the safety profile of ketorolac in infants age 0-3 months.  
 
Papacci et al previously reported 18 neonates to whom ketorolac was administered in a 
postoperative or postprocedural setting, reporting it to be safe and efficacious in this 
population.(6)  Others have studied these risks and complications of ketorolac in children and 
older infants. In a single center, prospective randomized controlled trial, Gupta et al evaluated 
the risk of bleeding complications related to ketorolac use for the treatment of postoperative 
pain in 75 infants and children undergoing congenital heart surgery.7 The median age of 
patients in this study was 10 months (range 2.5-174 months). Postoperative pain control 
consisted of ketorolac with opioid analgesics in one study arm, and opioid analgesics alone in 
the other study arm. The main outcome measured was bleeding complications as measured by 
chest-tube drainage, wound, and gastrointestinal bleeding. They demonstrated no significant 
differences between the two treatment arms with respect to any of these parameters, 
concluding ketorolac to be a safe and effective choice of alternate analgesia in treating 
postoperative pain in older infants and children undergoing congenital heart surgery.7  
 
A paucity of data exists regarding its use in neonates and young infants less than 3 months of 
age. One retrospective review of 53 patients <6 months of age who received postoperative 
ketorolac following cardiac surgery also included 11 patients who were <1 month of age.8 This 
review found an increase in blood urea nitrogen/serum creatinine (SCr) levels from baseline 
following the administration of ketorolac, although the levels remained within normal limits 
during the course of therapy. Four patients (7.5%) had minor bleeding episodes, none of 

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which resulted in significant changes in hemoglobin or platelet levels, or required the 
transfusion of blood products. A smaller, retrospective review of 10 infants less than 6 months 
of age also demonstrated that ketorolac reduces the opioid requirement following abdominal 
surgery and can be administered safely to infants of 37 weeks CGA or greater.1 And Papacci’s 
study reviewed the use of ketorolac in a neonatal setting in 18 infants whose average CGA 
was 37 +/- 4 weeks (range 25-38 weeks), and found no significant changes in hematological, 
renal, or hepatic parameters, and no resultant bleeding complications.6 While these 
conclusions appear promising for this very young age group, the numbers are quite small.  
2.2 
 Rationale: This is the first study of which we know to evaluate the use of ketorolac 
exclusively in this neonatal age group. This study will help to define the safety of the drug and 
its potential for adjuvant pain control in this age group. We hypothesize that ketorolac is safe 
and effective in infants > 37wks corrected gestational age and at least one week of age. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
Risks of ketorolac include the potential for bleeding events (1-3% in population), the risk of renal 
insufficiency (1-3% in population), and the risk of hypersensitivity reactions. These are accepted risks 
when using ketorolac in older infants, children, and adults. While these risks are small, the 
seriousness of such risks may be much greater and may involve the need for blood transfusions, 
additional procedures and/or reoperations, or additional laboratory or radiological studies.  
Bleeding episodes will be defined by following: 
1. Persistent bloody drainage from a nasogastric tube, resulting in a drop of hemoglobin of greater 
than or equal to 2g/dL (change of 1g/dL in hemoglobin may be explained by the infusion of 
perioperative crystalloid, and inthe abscence of hemodynamic instability would be considered within 
the acceptable standard deviation) 
2. Surgical site bleeding resulting in a drop of hgb >2g/dL from inital postop value, unless the patient 
has required crystalloid or fluid boluses other than PRBC totalling 60ml/kg or greater. 
3. Any hemodynamic instability associated with a drop of hemoglobin >2g/dL 
 
Several published criteria for adults and children exist to enable the practitioner to identify early signs 
of renal injury (9-11). Of these, the Pediatric modification of the Risk, Injury, Failure, Loss, End-Stage 
Renal Disease (p-RIFLE) criteria are probably the most reliable in this population, as this has been 
validated in children.  

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2.3.2 Known Potential Benefits 
Potential benefits include less postoperative pain, need for less opioid which potentially may 
lead to fewer days on the ventilator, faster return of bowel function, and shorter hospital stay. 

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3 
OBJECTIVES 
3.1 
Study Objectives 
The general purpose of this study is to characterize the safety profile of ketorolac in infants age 0-3 
months. During the study, data will also be collected evaluating the change in the need for opioids 
in patients who receive ketorolac versus those who receive placebo.  
Ketorolac 0.5mg/kg intravenously every 8 hrs for 72hrs will be administered versus an equivalent 
volume of 0.9% normal saline as placebo.  
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
Primary: The primary purpose of this study is to compare bleeding events in neonates who 
receive ketorolac and those who do not receive ketorolac. We hypothesize that ketorolac is 
safe and effective in infants > 37wks corrected gestational age and at least one week of age. 
Primary outcomes measured include bleeding events and renal injury.  
3.2.2 Secondary Outcome Measures 
Secondary: We intend to evaluate daily creatinine levels, pain scores, urine output per shift, 
platelet counts, hemoglobin levels, number of days on the ventilator, amount of opioid 
administered, blood pressure, and reintubation events on all patients in this study as 
secondary study points. 
. 

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4 
STUDY DESIGN 
This is a Phase II, single center, randomized controlled pilot study. Hospitalized patients one week of 
age to 3 months of age who undergo an abdominal or thoracic surgical procedure within the moderate 
or severe degree of pain category (see attached Table 1: postoperative pain categories) will be 
randomized to receive standard pain management regimens plus placebo (0.9% saline of equivalent 
volume) or ketorolac 0.5mg IV q8h x 72h plus standard pain management regimens. The 
postoperative management will be unchanged and at the discretion of the attending surgeon, as 
appropriate for the surgical procedure. The patients will be followed for 5 days, or 48hrs from the end 
of ketorolac therapy for primary and secondary endpoints. Ketorolac will be started within 24hrs of the 
end of the operative procedure. 
 
 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Annually, we see approximately 80 -100 patients who would be potential candidates for this study. 
The proposed sample size for this study is 50 patients, 25 in each group. We anticipate the time to 
completion of this study will be 1-2 years. The duration of subject participation will be 5 days. The 
parents or guardians of potential patients will be approached preoperatively by the study personnel for 
explanation of the study, its purpose, risks, and potential benefits. Consent will be obtained by one of 
the investigators of the study.   
 
5.1 
Subject Inclusion Criteria 
1. Infants gestational age >37 weeks corrected gestational age and greater than or equal to one 
week of age to 3 months of age  
2. Infants who are undergoing a surgical procedure on the abdomen or chest (cardiothoracic) 
3. The parent or guardian has given informed consent.  
 
5.2 
Subject Exclusion Criteria 
1. Gestational age <37 weeks 
2. Age less than one week or greater than 3 months of age 
3. Known renal disease/dysplastic kidneys 
4. Serum Creatinine >0.4 
5. Patients who have rising creatinine levels the day prior to surgery (increase of at least 1.5-fold 
from baseline) 
6. Patients who are currently receiving other potentially renal toxic drugs or drugs that may 
interfere with hemostatic pathways as part of their clinical care (including but not limited to 
hydrochlorothiazide, vancomycin, gentamicin, aspirin, TPA [except for use of thrombosed 
central venous catheters], enalapril, systemic heparin [except for use in central venous 
catheter flushes]) 
a. Furosemide will be allowable as is relevant particularly to postoperative cardiothoracic 
patients. UOP must be >1ml/kg/h while on receiving furosemide and study 
drug/placebo, and the patient will be under the constant supervision of a physician 
assessing patient perfusion 
7. Patients who undergo nephrectomy 
8. Patients with necrotizing enterocolitis 
9. Patients with a hemoglobin value <9g/dL 
10. Recent (within 3 months) GI bleeding, ulceration, and/or perforation  
11. Platelet count < 50,000 
12. Ongoing disseminated intravascular coagulation or history of intraventricular hemorrhage  
13. Recent use or current use of other nonsteroidal anti-inflammatory drugs (NSAIDS) besides 
aspirin (ASA)  
14. Allergy to ASA or other NSAIDS 

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5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
This trial is randomized. Patients will be randomized according to a fixed 1:1 allocation. The overall 
sample size will be 50 patients, 25 in each group. The randomization scheme will consist of a 
permuted block randomization in which the blocking factor varies randomly between 4 and 6.  
Randomization will be stratified by pain category (moderate and severe, refer to pain management 
guidelines).  
An observational arm was added for those patients who do not wish to be randomized. If consent is 
obtained for this arm of the study, then study staff will be allowed to follow and record clinical data as 
applicable and stated for this study. Patients will receive postoperative pain control as per the 
discretion of their primary provider. 
5.3.2 Masking Procedures 
The randomization strategy will be performed by an independent person to ensure investigator 
masking to the process.  
5.3.3 Reasons for Withdrawal 
Those who will monitor the data include the study staff physicians and pharmacist. The data to be 
monitored include any bleeding events, evaluation of renal function including BUN and Creatinine 
levels. These will be monitored on an individual patient basis at least daily. Additional outcomes as 
mentioned in primary and secondary outcomes section will be monitored.  
Bleeding events: Bleeding events will be closely monitored in the NICU setting. Daily CBC's are 
obtained during the postoperative period, and these will be recorded as data relevant to the study. 
Deviations in hemoglobin or platelet counts will be detected, and treated as is standard of care.  
Bleeding episodes will be defined by following: 
1. Persistent bloody drainage from a nasogastric tube, resulting in a drop of hemoglobin of greater 
than or equal to 2g/dL (change of 1g/dL in hemoglobin may be explained by the infusion of 
perioperative crystalloid, and in the absence of hemodynamic instability would be considered within 
the acceptable standard deviation) 
2. Surgical site bleeding resulting in a drop of hgb >2g/dL from initial postop value, unless the patient 
has required crystalloid or fluid boluses other than PRBC totalling 60ml/kg or greater. 
3. Any hemodynamic instability associated with a drop of hemoglobin >2g/dL 

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Renal injury: Several published criteria for adults and children exist to enable the practitioner to 
identify early signs of renal injury (9-11). Of these, the Pediatric modification of the Risk, Injury, 
Failure, Loss, End-Stage Renal Disease (p-RIFLE) criteria are probably the most reliable in this 
population, as this has been validated in children.  
 
Based upon these criteria, renal function will be monitored frequently. Based upon the following 
criteria, a patient will be unblinded and pulled from the study: 
1. Patients who are resuscitated but with continued postoperative UOP<0.5ml/kg/h persistent over 8 
hours  
2. A decrease in estimated creatinine clearance by 25%, in a well-resuscitated patient 
5.3.4 Withdrawals 
Subjects are free to withdraw from participating in the study at any time upon request.  
The patient will become unblinded and pulled from receiving the study drug or placebo if any bleeding 
events occur or if renal function worsens (rise in greater than 0.5mg/dL). However, events will still be 
recorded on the patient, and these patients will still be followed for the duration of the study (i.e. 5 
days or 72 hrs from the end of the study drug), or until resolution and or through treatment of an 
adverse event.  
In addition, an evaluation and possibly a change in the study protocol will be initiated due to safety 
concerns. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory 
drugs (NSAIDs) and supplied as a racemic mixture of [-]S and [+]R ketorolac tromethamine. 
Ketorolac tromethamine may exist in three crystal forms; all forms are equally soluble in water. 
Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The 
molecular weight of ketorolac tromethamine is 376.41 and the molecular formula is C19H24N2O6. 
6.1.1 Acquisition 
Ketorolac tromethamine will be obtained by the pharmacy department from Hospira, Inc.  
6.1.2 Formulation, Packaging, and Labeling 
Ketorolac tromethamine is supplied as a 30mg/mL clear to slightly yellow sterile solution for 
injection in a 1mL single-dose vial. The solution contains 10% (w/v) alcohol. 
6.1.3 Product Storage and Stability 
Ketorolac tromethamine will be stored at room temperature (20-25 degrees Celsius) in its 
original container and protected from light. The product will be maintained securely by the 
pharmacy department and stored separately from the general stock.  
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Dosage 
 
The dose of ketorolac is 0.5mg/kg given intravenously every 8 hours for 72 hours. The first 
dose will be given within 24hrs from the conclusion of the surgical procedure. A total of 9 
doses will be administered. 
 
Preparation & Blinding 
 
Subjects will be assigned to treatment or placebo in sequential order as indicated by the 
provided randomization scheme. The pharmacy will then aseptically prepare the blinded 
syringe of investigational product. Ketorolac will be diluted with 0.9% Sodium Chloride to a 

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concentration of 0.6mg/mL. Subjects assigned to placebo will be given 0.9% Sodium Chloride 
at a volume equivalent to the active product. 
 
All study syringes will be administered within 24 hours of preparation. 
6.3 
Modification of Study Intervention/Investigational Product for a 
Participant 
Dose modifications will not be performed, as this drug will be administered on a weight-based 
calculation. Patients who experience a bleeding episode or acute change in renal function as defined 
previously (Section 5.2.3) will not have dose modification, but will be pulled from the study.  
 
6.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
All investigational products will be maintained by the pharmacy department and stored separately 
from the general stock. Upon receipt of the product, an inventory will be performed and contents of 
the shipment verified. Accountability logs will be maintained by the pharmacy and indicate all 
investigational product that has been received, dispensed, and destroyed at the site.  
6.5 
Concomitant Medications/Treatments 
All current medications and therapies will be continued during this study with the exception of those 
listed in the exclusion criteria.  
 

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7 
STUDY SCHEDULE 
7.1 
Study Evaluations 
Written informed consent will be obtained from the eligible patient’s parent or guardian prior to their 
operative procedure. Consent will be obtained from one of the investigators listed on the study 
protocol. 
Eligible subjects will be randomized to receive standard pain management regimens plus placebo 
(0.9% saline of equivalent volume) or ketorolac 0.5mg IV q8h x 72h plus standard pain management 
regimens, post-operatively. The study drug will be started within 24hrs of the operative procedure.  
All subjects will undergo daily physical examinations by their operating surgeon and team (including 
nurse practitioners, surgical residents, surgical fellows, nursing staff). Days on the ventilator, 
reintubation events, blood urea nitrogen levels, creatinine levels, neonatal pain scores (NPASS), urine 
output per shift, platelet values, hemoglobin values, blood pressure, amount of opioid used, other 
medications patient is receiving, intraoperative issue/complications will be recorded.  
Patients will have daily laboratory tests including complete blood counts and chemistry panels as 
would be routine for their postoperative care.  
The following laboratory evaluations will be performed daily on patients enrolled in this study, as part 
of their routine postoperative care. Additional laboratory studies may be obtained as indicated by the 
patient’s condition.  Laboratory specimens will be obtained via heelstick, arterial line (if existent), or 
central venous catheter (if existent). Specimen volumes will be minimalized to 0.5ml per tube.  
Hematology:  hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet count. 
Biochemistry:  blood urea nitrogen, creatinine, electrolytes.  
Coagulation profile: protime, prothrombin time, INR 
 
No additional testing will be required by the study, unless signs of renal injury or bleeding events  
occur. 
 
7.2 
Follow-up  
The drug/placebo will be administered every 8 hours for 72 hours, unless the medication is stopped 
earlier due to an AE. Patients will be followed for 48 hours from the completion of the drug/placebo 
administration. After 48 hours, the study will be concluded for that patient. There will be no further 
follow-up evaluations or visits.  

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Specification of Safety Parameters 
Events will be collected during the duration of the study, which is 48 hours from the completion of the 
study drug/placebo. 
Bleeding episodes will be defined by following: 
• 
Persistent bloody drainage from a nasogastric tube, resulting in a drop of hemoglobin of 
greater than or equal to 2g/dL (change of 1g/dL in hemoglobin may be explained by the 
infusion of perioperative crystalloid, and in the absence of hemodynamic instability would be 
considered within the acceptable standard deviation) 
• 
Surgical site bleeding resulting in a drop of hemoglobin >2g/dL from initial postop value, 
unless the patient has required crystalloid or fluid boluses other than PRBC totalling 60ml/kg 
or greater. 
• 
Any hemodynamic instability associated with a drop of hemoglobin >2g/dL 
 
2. Renal injury will be defined by the following: 
• 
Patients who are resuscitated but with continued postoperative UOP<0.5ml/kg/h persistent 
over 8 hours  
• 
A decrease in estimated creatinine clearance by 25%, in a well-resuscitated patient 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
8.2.1 Adverse Events 
Adverse Event:  ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product regardless of its causal relationship to the 
study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product. The occurrence of an AE may come to the attention of study personnel 
during study visits and interviews of a study recipient presenting for medical care, or upon review by a 
study monitor.  
All AEs including local and systemic reactions not meeting the criteria for “serious adverse events” 
should be captured on the appropriate CRF. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis, which would include MD, PA, Nurse Practitioner, 
DO, or DDS), and time of resolution/stabilization of the event. All AEs occurring while on study must 

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be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution.  
Any medical condition that is present at the time that the patient is screened should be considered as 
baseline and not reported as an AE. However, if it deteriorates at any time during the study, it should 
be recorded as an AE. 
All AEs must be graded for severity and relationship to study product.  
Severity of Event:  All AEs will be assessed by the clinician using a protocol defined grading system. 
For events not included in the protocol defined grading system, than the following guidelines will be 
used to quantify intensity.  
Mild: events require minimal or no treatment and do not interfere with the patient’s daily activities. 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
Severe: events interrupt a patient’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating. 
Life threatening:  any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, ie, it does not include a 
reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE should be documented to allow an assessment of the duration of the 
event at each level of intensity to be performed. Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
Relationship to Study Products:  The clinician’s assessment of an AE's relationship to test article 
(vaccine or study drug) is part of the documentation process, but it is not a factor in determining what 
is or is not reported in the study. If there is any doubt as to whether a clinical observation is an AE, 
the event should be reported. All AEs must have their relationship to study product assessed using the 
terms: associated or not associated. In a clinical trial, the study product must always be suspect. To 
help assess, the following guidelines are used. 
• 
Associated – The event is temporally related to the administration of the study product and no 
other etiology explains the event. 
• 
Not Associated – The event is temporally independent of study product and/or the event appears 
to be explained by another etiology. 
8.2.2 Serious Adverse Events 
Serious Adverse Event (SAE): An SAE is defined as an AE that meets one of the following 
conditions: 
Death during the period of protocol defined surveillance 
Life-threatening event (defined as a subject at immediate risk of death at the time of the event) 

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An event requiring inpatient hospitalization or prolongation of existing hospitalization during the period 
of protocol defined surveillance  
Results in a persistent or significant disability/incapacity 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
All SAEs will be: 
• 
recorded on the appropriate SAE source document 
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician 
8.2.3 Procedures to be followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings 
Bleeding will be closely monitored in the NICU setting. Daily CBC's are obtained during the 
postoperative period, and these will be recorded as data relevant to the study. Deviations in 
hemoglobin or platelet counts will be detected, and treated as is standard of care. If concern arises 
about the drug, the patient will be unblinded and pulled from receiving the study drug or placebo. 
However, events will still be recorded on the patient. Collection of laboratory data should be limited to 
those laboratory parameters that are relevant to safety, study outcome measures, and/or clinical 
outcome.  
8.3 
Reporting Procedures 
8.3.1 Regulatory Reporting for Studies Conducted Under a Sponsor-Investigator 
IND 
Following notification to the investigator, the Sponsor Investigator, will report events that are both 
serious and unexpected and that are associated with study product(s) to the Food and Drug 
Administration (FDA) within the required timelines as specified in 21 CFR Part 312.32: fatal and life-
threatening events within 7 calendar days (by phone or fax) and all other SAEs in writing within 15 
calendar days. All serious events designed as “not associated” to study product(s), will be reported to 
the FDA at least annually in a summary format. 
 

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9 
CLINICAL MONITORING 
Site monitoring is not applicable for this single center pilot study. 
 

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10 
STATISTICAL CONSIDERATIONS 
10.1 Study Hypotheses 
We hypothesize that ketorolac is safe and effective in infants > 37wks corrected gestational 
age and at least one week of age.  
10.2 Sample Size Considerations 
This is a pilot study for safety. There are no statistical considerations for these small numbers. This 
study will hopefully provide some background data for a large scale, multi-center study with statistical 
significance.  
 
 

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11 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
11.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set forth 
in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research of the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal 
Regulations 25691 (1997).   
11.2 Institutional Review Board 
The study protocol and consent forms and any other related documents will undergo IRB review and 
the study will not be initiated until Nationwide Children’s Hospital’s IRB approval has been obtained. 
Any amendments to the protocol or consent materials will also be approved before they are placed 
into use. 
11.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation. Extensive discussion of risks and 
possible benefits of this therapy will be provided to the parents or guardians of the subjects. Consent 
forms describing in detail the study interventions/products, study procedures, and risks are given to 
the parent or guardian of the subject and written documentation of informed consent is required prior 
to starting intervention/administering study product. Consent forms will be IRB-approved and the 
parent or guardian of the subject will be asked to read and review the document. Upon reviewing the 
document, the investigator will explain the research study to the parent or guardian of the subject and 
answer any questions that may arise. The subject’s parent or guardian will sign the informed consent 
document prior to any procedures being done specifically for the study. The parent or guardian of the 
subjects should have the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. The parent or guardian of the subjects may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
parent or guardian of the subjects for their records. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected 
if they decline to participate in this study. 
11.3.1 Informed Consent/Assent Process (in Case of a Minor) 
Assent is not applicable to this patient population.  

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11.4 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 
11.5 Study Discontinuation 
In the event that the study is discontinued, the subjects will receive ketorolac at the discretion of their 
treating physician.  

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12 
DATA HANDLING AND RECORD KEEPING 
12.1 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. Adverse events must be graded, assessed 
for severity and causality, and reviewed by the PI or designee. 
Data collection is the responsibility of the clinical trial staff under the supervision of the PI. During the 
study, the investigator must maintain complete and accurate documentation for the study. 
12.2 Data Capture Methods 
Clinical data, including AEs, concomitant medications, and clinical laboratory data will be entered into 
a password protected data. Clinical data will be entered directly from the source documents.  
12.3 Types of Data 
Data for this study will include safety, laboratory, and outcome measure. 
12.4 Study Records Retention 
Study documents should be retained per Nationwide Children’s Hospital policy.  
12.5 Protocol Deviations 
Each patient will be reviewed actively while on the study by the study staff. A protocol deviation is any 
noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), or Manual of Procedures 
requirements. The noncompliance may be either on the part of the subject, the investigator, or the 
study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. The safety of the patient/subject will not be compromised by the study 
protocol.  

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13 
PUBLICATION POLICY 
 
Following completion of the study, the investigator is expected to publish the results of this research in 
a scientific journal.  The International Committee of Medical Journal Editors (ICMJE) member journals 
have adopted a trials-registration policy as a condition for publication. This policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov*, which is sponsored by 
the National Library of Medicine. Other biomedical journals are considering adopting similar policies. 
 
 
 
*Journal Citation: 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement from the 
International Committee of Medical Journal Editors. N Engl J Med. 2004;351:1250-1. 

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14 
LITERATURE REFERENCES 
1. RS Burd, JD Tobias. Ketorolac for pain management after abdominal surgical procedures in 
infants. Southern Medical Journal 2002; 95:331-333. 
2.  JP Purday, CC Reichert, PM Merrick. Comparative effects of three doses of intravenous 
ketorolac or morphine on emesis and analgesia for restorative dental surgery in children. Can 
J Anaesth 1996; 43:221-225. 
3.  CP Eberson, DM Pacicca, MG Ehrlich. The role of ketorolac in decreasing length of stay and 
narcotic complications in the postoperative pediatric orthopedic patient. J Ped Orthoped 1999; 
19:688-694. 
4.  TN Dawkins, CA Barclay, RL Gardiner, CD Krawczeski. Safety of intravenous use of ketorolac 
in infants following cardiothoracic surgery. Cardiol Young 2009; 19:105-108. 
5. H Kokki. Nonsteroidal anti-inflammatory drugs for postoperative pain. Pediatr Drugs 2003; 
5:103-123. 
6. P Papacci, G DeFrancisci, T Iacobucci, C Giannantonio, MP deCarolis, E Zecca, C Romagnoli. 
Use of intravenous ketorolac in the neonate and premature babies. Ped Anesth 2004; 14:487-
492. 
7. A Gupta, C Daggett, S Drant, N Rivero, A Lewis. Prospective randomized trial of ketorolac after 
congenital heart surgery. J Cardiothor Vasc Anesth 2004; 18:454-457. 
8. BS Moffett, TI Wann, KE Carberry, AR Mott. Safety of ketorolac in neonates and infants after 
cardiac surgery. Ped Anesth 2006; 16:424-428. 
9. M Zapitelli. Epidemiology and Diagnosis of Acute Renal Injury. Seminars in Nephrology; 2008; 
28:436-446 
10. R Mehta, J Kellum, S Shah, et al. Acute Kidney Injury Network: report of an initiative to 
improve outcomes in acute kidney injury. Critical Care; 2007; 11:R31. 
11. M Zappitelli, C Parikh, A Akcan-Arikan, et al. Ascertainment and Epidemiology of Acute Kidney 
Injury Varies with Definition Interpretation. Clin J Am Soc Nephrol. 2008; 3:948-954 

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15 
SUPPLEMENT/APPENDICES  
15.1 Table 1: Pharmacological management of post-operative pain 
associated with common neonatal surgical procedures. 
Degree of Pain 
Surgeries included 
Post-Op Pain Management 
Potential for Severe Pain 
Closure gastroschisis/ omphalocele under 
tension 
Complicated NEC 
CDH repair 
Exploratory laparotomy 
TEF/EA repair 
Nissen fundoplication / Gastrostomy tube 
Bowel re-anastamosis 
Wound debridement 
Cloacal exstrophy repair 
Thoracotomy 
Open abdomen/compartment syndrome 
Open liver biopsy / cholangiogram 
PDA ligation 
Tracheostomy 
 
1. 
Escalation: increased opiate dosing a 
minimum of 50% & increase PRN opiate 
dose / evaluate for addition of  ketolorac,  
 
2. 
continuous infusion opiate + PRN 
opiate for breakthrough pain  
 
               Morphine 0.05 mg/kg/hr +  
               morphine 0.05 mg/kg q1hrs  
               prn   
               OR 
               Fentanyl 2 mcg/kg/hr + 
               fentanyl 2 mcg/kg q1hr prn   
               Plus 
                
3. 
De-escalation: decrease infusion 50% or 
change to scheduled intermittent opiate 
+ PRN opiate for breakthrough pain  
 
Potential for Moderate 
Pain 
Closure of gastroschisis/omphalocele-no 
tension 
Repair incarcerated/giant hernia 
Abdominal drain or chest tube insertion 
Myelomeningocele repair 
Colostomy  
Primary laparoscopic pull through   
Large cystic hygroma resection 
 
1. 
Escalation: change to continuous 
infusion opiate 
 
2. scheduled intermittent opiate + PRN   
opiate for breakthrough pain  
 
 
       Morphine 0.05 mg/kg/dose  
       q3hrs  +  morphine 
       0.05 mg/kg/dose q1prn 
       
3. 
De-escalation: scheduled APAP  ± PRN 
opiate 
 
Potential for Mild Pain 
Uncomplicated inguinal hernia  
Perineal approach for Hirschsprung’s 
disease 
Perineal repair of imperforate anus/ 
anoplasty   
VP / subgaleal shunt placement 
Retinal laser surgery 
Gastrostomy tube insertion 
 
 
1. 
scheduled opiate + PRN APAP  
 
2. 
scheduled APAP* + prn opiate for 
breakthrough pain 
 
      scheduled APAP* + morphine  
      0.05 mg/kg/dose q1hrs prn         
 
3. 
non-pharmacologic 
*APAP = acetaminophen dosing based on age (see table 2)  

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15.2 Table 2 
 
Non-opiod analgesics 
 
Acetaminophen supp 
LD: 25-40 mg/kg  
MD: <28 wks: no data 
         28-32 wks: 20mg/kg q12° (max 40mg/kg/day) 
         32-36 wks or ≥37 wks and <10 days old: 15mg/kg q8° (max 60mg/kg/day)  
         ≥37 wks and >10 days old: 20mg/kg q6-8° (max 90mg/kg/day) 
Note: Use caution in patients with liver abnormalities and/or hyperbilirubinemia.  A 
maximum of 24 hours of APAP can be used in this population unless a specialist is 
consulted. 
Ketorolac 
>37 weeks and > 1 weeks of age  0.5mg/kg q8° 
> 44 weeks may increase to 0.5 mg/kg/dose q6hrs if needed 
maximum of 5 days of therapy  
*do not use the first week of life 
*do not use is estimated CrCl <30 ml/min 
Note: DO NOT USE in patients with history of GI perforation, ulcer, 
thrombocytopenia, liver dysfunction,and/or bleeding due to increased risk of GI 
bleeding8   
 
  References: 
1. 
Acute pain management: operative or medical procedures and trauma. I. Agency for Health Care Policy and Research. Clin Pharm 1992;11:309-31. 
2. 
American Academy of Pediatrics, Committee on Psychosocial Aspects of Child and Family Health, American Pain Society, Task Force on Pain in 
Infants, Children, and Adolescents. Pediatrics. 2001;108:793-97.  
3. 
Anand KJ and the International Evidence-Based Group for Neonatal Pain.  Consensus statement for the prevention and management of pain in the 
newborn.  Arch Pediatr Adolesc Med. 2001;155:173-180. 
4. 
Berde C, Jaksic T, Lynn AM, Maxwell LG, Soriano SG, Tibboel D.  Anesthesia and analgesia during and after surgery in neonates.  Clin Ther. 
2005;27:900-21. 
5. 
Burd RS, Tobias JD.  Ketorolac for pain management after abdominal surgical procedures in infants.  South Med J. 2002;95:331-33. 
6. 
Ketorolac tromethamine injection USP [product information].  Bedford, OH.  Bedford Laboratories, Jan 2008.   
7. 
Khurana R, Hall W, Anand KS.  Treatment of pain and stress in the neonate: when and how.  NeoReviews. 2005;6:e76-e86. 
8. 
Lexi-Comp Online.  http://www.crlonline.com/srlsq/servlet/crlonline.  Lexi-Comp, Inc.  1978-2008 (accessed 2008 Jan 15). 
9. 
Menon G, Anand KJ, McIntosh N.  Practical approach to analgesia and sedation in the neonatal intensive care unit.  Semin Prerinatol. 1998;22:417-
24. 
10. 
Pain and Sedation Exploratory Group.  Potentially better practices for reducing pain in infants in the NICU.  Vermont Oxford Network Tools for 
Improvement Series;1-77.