A Prospective, Open-label, Nonrandomized Efficacy and Safety Trial of Intranasal Ketorolac in Emergency Department Patients for the Treatment of Acute Pain
Phase: NA
Conditions: Other Acute Pain
Sponsor: The Cleveland Clinic

PROTOCOL: INTRANASAL KETOROLAC 
Clinical Study Protocol #S4 September 21, 2011 
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Unique Protocol ID: LUI-S4  
Brief Title: An Efficacy and Safety Trial of Intranasal 
Ketorolac in Emergency Department Patients for 
the Treatment of Acute Pain (Sprix)   
Official Title: A Prospective, Open-label, Nonrandomized 
Efficacy and Safety Trial of Intranasal Ketorolac 
in Emergency Department Patients for the 
Treatment of Acute Pain   
 
Protocol: Version 4.0/ September 21, 2011 
 
Principal Investigator: Sharon E. Mace, MD 
 
Sponsor: Luitpold Pharmaceuticals, Inc 

PROTOCOL: INTRANASAL KETOROLAC 
Clinical Study Protocol #S4 September 21, 2011 
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PROTOCOL NUMBER 1 
 
Clinical Study Protocol #S4 
 
 
A Prospective, open-label, nonrandomized efficacy and safety trial of intranasal ketorolac 
in emergency department patients for the treatment of acute pain 
 
 
Product: 
Ketorolac (Sprix) 
Version/Date: 
Version 4.0/September 21, 2011 
Study Design: 
Prospective, open-label, nonrandomized 
efficacy and safety trial 
Study Clinical Site 
Cleveland Clinic 
9500 Euclid Avenue, E-19 
Emergency Services Institute 
Cleveland, Ohio 44195 
Study’s Principal Investigator 
Sharon E. Mace, MD, FACEP, FAAP 
Professor of Medicine 
Cleveland Clinic Lerner College of 
Medicine, Case Western Reserve 
University 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP) Guidelines, and all other applicable regulatory components. 
 
 
 

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TABLE OF CONTENTS 
 
             BRIEF ABSTRACT 
 
1.         INTRODUCTION……………………………………………………………. 
 
1.1 Background………………………………………………………………… 
1.2 Summary of Clinical Studies……………………………………………… 
1.3 Risk-Benefit………………………………………………………………… 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS ………………………………….. 
2.1Objectives…………………………………………………………………..... 
2.1.1 Primary Objective…………………………………………………………. 
2.1.2 Secondary Objective………………………………………………………. 
2.2 Variables…………………………………………………………………… 
2.2.1 Primary Efficacy Variable………………………………………………… 
2.2.2 Secondary Efficacy Variables …………………………………………..... 
2.2.3 Safety Variables …………………………………………………………… 
2.2.3.1  Primary Safety Variables………………………………………………. 
2.2.3.2  Secondary Safety Variables…………………………………………….. 
 
3. 
INVESTIGATIONAL PLAN 
 
3. 1 Overall Study Design and Plan……………………………………………… 
3.2   Study Population…………………………………………………………….. 
3.2.1 Description………………………………………………………………… 
3.2.2 Inclusion Criteria…………………………………………………………. 
3.2.3 Exclusion Criteria………………………………………………………… 
3.3 Rationale for Study Design………………………………………………. 
 
4. 
STUDY TREATMENTS 
 
4.1 Medication(s) for study treatment………………………………………….. 
4.2 Method for Application of Ketorolac (Sprix) for the Treatment of Acute 
Pain…………………………………………………………………………….. 
4.3 Storage, Handling, and Administration……………………………………... 
4.4 Packaging and Labeling……………………………………………………… 
4.5 Study Treatment Accountability…………………………………………….. 
4.6 Treatment Compliance……………………………………………………….  

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Clinical Study Protocol #S4 September 21, 2011 
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5.   
SCHEDULE AND DESCRIPTION OF STUDY PROCEDURES 
 
5.1 Study Procedures……………………………………………………………... 
5.1.1 Pre-Study Period……………………………………………………………. 
5.1.1.1 Present to the Clinical Site……………………………………………….. 
5.1.2 Informed Consent…………………………………………………………... 
5.1.3. Patient Screening and Subject Log……………………………………….. 
5.1.3.1 Screening Assessments…………………………………………………… 
5.1.4 Study Treatment…………………………………………………………… 
5.1.4.1 Site Assessment…………………………………………………………… 
5.1.4..2 Study Pain Assessments………………………………………………….  
5.1.4..3 Study Questionnaires……………………………………………………. 
5.1.4.4. Standard-of-Care Procedures: Pain Management…………………….. 
5.1.5 Description and Documentation of Study Procedures……………………  
5.1.5.1 Study Number…………………………………………………………….. 
5.1.5.2 Demographics…………………………………………………………….. 
5.1.5.3 Medical History…………………………………………………………… 
5.1.5.3 Medications during the Study……………………………………………. 
5.1.5.4 Intranasal Ketorolac (Sprix) Administration during the Study……….. 
5.1.6 Efficacy Assessments……………………………………………………….. 
5.1.6.1 Pain Assessments…………………………………………………………. 
5.1.6.2. Patient Questionnaires…………………………………………………… 
5.1.6.3 Health Care Provider‘s Questionnaire(s)……………………………….. 
5.1.6.4 Safety Assessments……………………………………………………….. 
5.1.6.5 Site Assessments: Clinical………………………………………………... 
5.1.6.6 Side Effects/Adverse Events………………………………………………  
5.2 Protocol Deviations…………………………………………………………… 
5.3 Study Withdrawal Criteria…………………………………………………... 
5.4 Discontinuation of Study Treatment/Early Release from the Study………. 
5.5 Withdrawal for the Study……………………………………………………. 
5.6 Noncompliance/Replacement………………………………………………… 
 
6. 
DEFINITIONS AND DESCRIPTIONS OF ASSESSMENTS AND 
ENDPOINTS 
 
6.1 Pharmacokinetic/Pharmacodynamic Endpoints and Assessments………... 
6.2 Efficacy Variables…………………………………………………………….. 
6.2.1 Primary Efficacy Variable…………………………………………………. 
6.2.2 Secondary Efficacy Variables……………………………………………… 
6.3 Safety Variables………………………………………………………………. 
6.3.1 Primary Safety Variable……………………………………………………  
6.3.2 Secondary Safety Variables………………………………………………...  
6.3.3 Adverse Events……………………………………………………………… 
6.3.3.1 Definitions…………………………………………………………………. 

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6.3.3.2 Serious Adverse Event…………………………………………………….  
6.3.3.3 Reporting………………………………………………………………….. 
 
 
7. 
DATA ANALYSIS AND STATISTICAL METHODOLOGY   
 
7.1 Planned Sample Size………………………………………………………….. 
7.2 Efficacy………………………………………………………………………… 
7.3 Safety…………………………………………………………………………... 
 
8. 
 TERMINATION OF THE STUDY 
 
9.  
ADMINISTRATION AND REGULATORY CONSIDERATIONS 
 
9.1 Prior to Initiation of the Study………………………………………………. 
9.2 Institutional Review Board…………………………………………………... 
9.3 Informed Consent/Authorization…………………………………………… 
9.4 Duties of the Investigator……………………………………………………. 
9.5 Monitoring……………………………………………………………………. 
9.6 Study Records………………………………………………………………… 
9.7 Records Retention…………………………………………………………….   
9.8 Subject Privacy/Authorization……………………………………………….  

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BRIEF ABSTRACT 
 
INTRODUCTION: Pain is a common reason for individuals to seek health care, 
especially emergency care. Ketorolac has numerous advantages over other pain 
medications, especially the opioids. The intranasal administration of ketorolac has been 
shown to be safe and effective in the treatment of postoperative pain following major 
abdominal surgery and post dental surgery, but there have been no studies evaluating the 
use of intranasal ketorolac for the treatment of acute pain in the emergency department. 
 
METHOD: Twenty-five adults who are in the ED for an acute episode of pain will 
receive a single dose of intranasal ketorolac. Their pain before and after receiving the 
ketorolac will be measured by pain scales e.g. the numeric rating scale (NRS). The 
efficacy will be assessed by several measures including pain relief, pain intensity 
difference, global pain evaluation, global assessment of analgesia, and the summed pain 
intensity difference (SPID). This will allow for assessment of meaningful pain relief and 
the time to pain relief. The safety will be assessed by documentation of adverse events, 
vital signs, and clinical assessment of the nasal mucosa before and after the intranasal 
administration of the drug. The efficacy, tolerability and safety will also be assessed by 
patient and health care provider questionnaires. 
 
PRIMARY OBJECTIVES:  To determine the efficacy of ketorolac in an acute care 
setting, the emergency department (ED). 
 
SECONDARY OBJECTIVES: To determine the safety and tolerability of ketorolac in an 
acute care setting, the ED. 
 
PATIENT POPULATION: Adults: 18- 64 years of age, previously healthy men and 
nonpregnant women, with acute pain (e.g. an acute orthopedic injury such as a fracture or 
a kidney stone) being seen in the emergency department.  
 
INTERVENTION: Single dose of intranasal ketorolac 
 
CLINICAL MEASUREMENT: Pain scale (numeric rating scale = NRS) will be 
completed before and after giving intranasal ketorolac. Pain relief (e.g. numeric pain 
scale), global pain evaluation, pain intensity differences, global anesthesia (global pain 
relief) and patient/health care questionnaires will be completed. 
 
OUTCOME: Decrease in pain by several measures including NRS after intranasal 
ketorolac is given, tolerability and safety evaluation  
 
 
 
 
 
 

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INTRANASAL KETOROLAC FOR THE TREATMENT OF ACUTE PAIN IN 
THE EMERGENCY DEPARTMENT 
 
1. INTRODUCTION 
 
1.1 Background 
 
Pain is the number one reason for seeking health care. Patients are commonly seen in the 
emergency department (ED) with acute pain. Considering all ED visits, pain is the most 
common chief complaint. Up to 70% of ED visits are related to pain as the rationale for 
the ED visit.1 Moreover, this does not include those individuals seeking care in urgent 
care centers, clinics or offices.  
 
Ketorolac is effective in relieving pain. It has several advantages over other pain 
medications, including the opioids. First, since it does not bind to the opiate receptors 
(mu, kappa, and delta), it is nonaddicting. However, a 30 mg dose of ketorolac given 
intramuscularly has a demonstrated analgesic effect between that obtained with morphine 
6 mg and 12 mg. Next, it also has the additional safety advantage in that it avoids the side 
effects of the opioids including the fact that it does not cause respiratory depression or 
hypotension. 
 
The intranasal route of administration has numerous benefits over other methods of drug 
administration. The intravenous (IV) route of drug administration is painful, takes time to 
establish, costs more to administer, and can have an initial high peak of drug effect 
(Tmax) which can have unwanted side effects/complications (e.g. rapid peak with an 
increased possibility of complications such as hypotension and respiratory depression).2 
The intramuscular route is also quite painful.2 Orally administered medications take time 
to be absorbed and exert a maximal effect, have a variable absorption from the 
gastrointestinal tract, and may not be an option in patients with vomiting, diarrhea, mal-
absorption or other gastrointestinal disorders.2 
 
The intranasal route is easy to administer, is nonpainful (unlike an intramuscular shot or 
IV line insertion), has a rapid onset, and a more level or consistent efficacy over time 
with less of a sudden peak than IV and likely, lesser side effects/complications than IV.  
 
1. 
Mace SE, Murphy MF. Pain management and procedural sedation: definitions and 
clinical applications. In: Mace SE, Ducharme J, Murphy MF (eds). Pain 
management and Sedation: Emergency Department Management. 1st ed. New 
York: McGraw-Hill Co, 2006; Ch. 3, pp. 7-14. 
2. 
Mace SE. Alternate routes for the systemic delivery of analgesics and sedatives. 
In: Mace SE, Ducharme J, Murphy MF (eds). Pain management and Sedation: 
Emergency Department Management. 1st ed. New York: McGraw-Hill Co, 2006; 
Ch. 47, pp. 366-380. 
 
 

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1.2 Summary of Clinical Studies with Intranasal Ketorolac 
 
1.  Singla N, Singla S, Moodie J, Brown C. Intranasal ketorolac for acute postoperative 
pain. Current Medical Research and Opinion 2010; 26(8): 1915-1923. 
 
This was a double-blind, randomized controlled, multicenter (6 sites in the United States 
and New Zealand) trial in 321 adults (ages18 to 64 years) undergoing major open 
abdominal surgery under general anesthesia . Patients were randomized to receive either  
intranasal ketorolac 31.5 mg or placebo, administered as one spray (100 µL) into each 
nostril, every 6 hours for the first 48 hours following surgery, then up to four times a day. 
After surgery, patients received intravenous opioid until they were comfortable. Then 
pain intensity (PI) ratings using a visual analog scale (VAS) of 0 to 100 mm where 0 
represents no pain and 100 is the worst pain imaginable were done. When PI ratings were 
at least 40 on the VAS, patients received either intranasal ketorolac or placebo; in 
addition to patient access to intravenous morphine via patient controlled analgesia (PCA) 
through at least 48 hours for pain not controlled by the study drug.  
 
Results: Efficacy 
 
Mean pain intensity VAS scores were significantly lower in the intranasal ketorolac 
group compared to placebo at 20 minutes (55.4 ± 1.9 vs. 60.5 ± 1.3, p=0.014), at 60 
minutes (47.0 ± 1.5 vs. 53.5 ± 2.1, p= 0.008), 2 hours (43.3 ± 1.6 vs. 49 ± 2.2, p= 0.026), 
3 hours (36.5 ± 1.5 vs. 44.2 ± 2.2, p= 0.002), 6 hours (29.8 ± 1.4 vs. 34.5 ± 2.2, p= 
0.0038), 18 hours (29.0 ±1.5 vs.  32.3 ± 2.3, p= 0.016), 24 hours (26.4 ± 1.5 vs. 32.3 ± 
2.3, p= 0.016), and 30 hours (24.3 ± 1.5 vs. 29.5 ± 2.2, p=0.037). The mean pain intensity 
difference (PID), calculated as the baseline VAS minus the post treatment VAS (PID = 
baseline VAS – post treatment VAS),  was significantly higher for the ketorolac group 
than for the placebo at 20 minutes (p=0.010), 1 hour (p= 0.005), 2 hours (p= 0.034), and 
3 hours (p= 0.017) The 6 hour summed pain intensity difference (SPID6) was 
significantly higher for the intranasal ketorolac group compared to the placebo group 
least square means (± SE) 117.4 (± 7.7) vs.  89.9 (± 10.6), p = 0.032; difference in means 
27.6, (95% CI 2.5 – 52.7). The quality of analgesia was rated by patients (where 0 = poor, 
1 = fair, 2 = good, 3 = very good, and 4 = excellent) as statistically better in the intranasal 
ketorolac group compared to the placebo group at all time points from 20 minutes to 24 
hours except for the 40 minute and 6- hour time points. The global assessment of pain 
control was significantly better in the intranasal ketorolac group (where 0 = poor, 1 = fair, 
2 = good, 3 = very good, and 4 = excellent), with the mean (± SE) being 2.6 (± 0.06) vs. 
2.4 (± 0.09), p = 0. 009.  The need for rescue medication was less for the intranasal 
ketorolac group than for the control. Morphine use was decreased by 34% for the 0 – 72 
hours (82 mg vs.121 mg), although the difference was not statistically significant because 
of a decreased need for analgesia with the use of intranasal ketorolac.  All of this data 
indicates better analgesia with intranasal ketorolac than for the placebo group  
 

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Results: Safety and Tolerability  
 
The percent of patients with at least one adverse event were similar in the two treatment 
groups (ketorolac 93% (198/214) vs. placebo 96% (103/107). Adverse events were 
characteristic of those following major abdominal surgery. Common adverse events were 
nausea, constipation, vomiting, and headache. There was a trend (≥ 5% difference) for 
reduced incidences of nausea, constipation, pyrexia, and tachycardia in the ketorolac 
group compared to placebo. The majority of patients had mild adverse events with the 
proportion of adverse events similar in the ketorolac vs. the placebo group (84% vs. 
79%). The rate of serious adverse events was identical at 6% in the two groups, of which 
89% were considered not related to the study drug.  Serious adverse events included: 
ileus, nausea and vomiting, post-procedural complications, and infections. No patient had 
gastrointestinal bleeding, surgical bleeding, or renal insufficiency considered related to 
the study drug.  
 
Conclusion  
 
Intranasal toradol was well-tolerated, provided effective pain relief within 20 minutes, 
and reduced the need for opioid analgesia use. “While intranasal ketorolac was assessed 
in an inpatient, conventional surgery setting in this study, intranasal ketorolac use may 
have more relevance for use in outpatient settings and ambulatory surgery or fast-track 
surgical procedures.” 
 
2. Grant GM, Mehlisch DR. Intranasal ketorolac for pain secondary to third molar 
impaction surgery: a randomized, double-blind, placebo-controlled trial. Journal Oral 
Maxillofacial Surgery 2010; 68: 1025-1031. 
 
This was a single center, double-blind, randomized controlled trial of 80 adult patients (≥ 
18 years of age) undergoing third molar impaction surgery. Patients were randomized to 
receive either intranasal ketorolac (31.5 mg) or intranasal placebo.  Efficacy was 
measured using summed pain intensity difference (SPID) score over the first eight hours 
after dosing (primary efficacy variable), and secondary efficacy variables: pain intensity 
(visual analog scale = VAS) , total pain relief (TOTPAR) and global pain evaluation up 
to eight hours after dosing. Pain intensity was measured with a using a 100 mm VAS 
scale with 0 = no pain and 100 = worst pain possible.  Pain intensity difference (PID) 
scores were calculated by subtracting each VAS post dose score from the baseline VAS 
score or PID = baseline VAS – post dose VAS. The SPID is calculated by taking a 
weighted sum of the PID scores. 
  
The safety was assessed by assessing spontaneously reported adverse events and clinical 
signs, hematology and clinical chemistry throughout the treatment period and at a follow-
up visit.  
 

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Results: Efficacy 
 
The decrease in pain was significantly greater for the intranasal ketorolac than for the 
placebo. The results for intranasal ketorolac vs. intranasal placebo were mean (± SE) 
SPID8: 136.7 (± 33.0) vs. 105.2 (± 29.1), p< 0.001; SPID4: 90.3 (± 16.4) vs. 46.7 (± 
13.5), p< 0.001; SPID6: 120.5 (± 24.7) vs. 76.7 (± 21.1), p < 0.001; TOTPAR4: 6.7 
(±0.8) vs. 1.7 (± 0.4), p < 0.001; TOTPAR6 9.7 (± 1.2) vs. 2.4 (± 0.7), p < 0.001; 
TOTPAR8:12.0 (± 1.6) VS. 3.1 (± 0.9), p<0.001. The time to perceptible pain relief (time 
to onset in minutes) was 21.5 for intranasal ketorolac vs. 480 for intranasal placebo, 
p<0.001. The time to meaningful pain relief (time to onset in minutes) was 66.0 for 
intranasal ketorolac vs. 480 for placebo, p< 0.001. The need for rescue medication 
(minutes) was 360.0 for intranasal ketorolac vs. 95.5 for intranasal placebo, p< 0.001. 
The patient global assessment of pain control 8 hours after the intranasal ketorolac or 
placebo was also significantly better for ketorolac with a mean score of 1.9 ± 0.2 vs. 0.5 
± 0.1, p < 0.001. 
 
Results: Safety and Tolerability 
 
More adverse events were reported in the placebo group (8 patients with 10 events) than 
in the ketorolac group (3 patients with 3 events). All events were mild or moderate in 
severity and no serious events were reported. Headache occurred in 8 subjects (placebo 
n=5; ketorolac n=3) and was the only adverse event in the ketorolac group. In addition to 
the headache, 3 patients in the placebo group reported nausea, 1 had vomiting, and 1 had 
dizziness. There were no clinically relevant differences between the treatment groups in 
clinical assessments at the follow-up visit.  
 
Conclusion 
 
A single 31.5 intranasal dose of ketorolac provided rapid and effective pain relief and 
was well tolerated in oral surgery patients for up to 8 hours 
 
3. Brown C., Moodie J, Bisley E, Bynum L. Intranasal ketorolac for postoperative pain: a 
phase 3, double-blind, randomized study. Pain Medicine.  2009; 10(6): 1106-1114. 
 
This was a two hospital, phase 3, double-blind, randomized controlled study of 300 adults 
(N=199 Ketorolac, N= 101 placebo) undergoing surgery (abdominal or orthopedic or 
breast reconstruction surgery). Post-operative patients were randomized to either 30 mg 
(100 µl) intranasal ketorolac or intranasal placebo as a single dose or multidose regimen 
administered 3 times per day up to 5 days with backup analgesia as needed. Patients had 
access to morphine sulfate by patient-controlled analgesia (PCA). The primary efficacy 
endpoint was the single-dose summed pain intensity difference score (PID) at 6 hours. 
Secondary efficacy endpoints were pain intensity (PI) ratings using a visual analog scale 
(VAS) of 0- 100 mm where 0 represents no pain and 100 is the worst pain imaginable. 
PID scores were calculated by subtracting the post-treatment PI score from the baseline 

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score, where the baseline score was the PI rating made prior to the first dose of study 
medication on Day 1. SPID = Baseline PI – Post-treatment PI = Baseline VAS – 
Postreatment VAS. The summed PID (SPID) was determined from weighted PID scores 
over 6 hours, where the weight is proportional to the time elapsed since the previous 
rating. Secondary endpoints included onset, peak effect, quality of analgesia, and 
duration of analgesia in the first 6 hours after single dose study drug administration. 
Onset of analgesia was determined by the patients clicking a stopwatch at the time they 
reached “meaningful” pain relief, where meaningful relief was defined as “relief that 
definitely makes you feel better”. Peak effect was the maximum PID score prior to 
restarting morphine sulfate by PCA. Quality of analgesia was rated using a five-point 
categorical scale where 0 = poor, 1= fair, 2 = good, 3 = very good, and 4 = excellent.  
The duration of analgesia was the time from the first dose of study medication on Day 1 
to the first dose of morphine sulfate after restarting PCA. For the multidose regimen, 
efficacy assessments were global evaluation of pain control, mean total morphine sulfate 
use, and quality of analgesia ratings. The global assessment of pain control was rated by 
patients at the end of each day using a five-point categorical scale, where 0= poor, 1= 
fair, 2 = good, 3 = very good and 4 = excellent.  Safety was assessed from spontaneously 
reported adverse events and measurement of adverse clinical signs. Hematology and 
clinical chemistry measurements were made at the termination visit, which occurred 
between 4 and 9 days after the start of dosing. 
 
Results: Efficacy 
 
The SPID6 score was significantly higher for the ketorolac group than for the placebo 
group. The mean (± SE) was 83.8 (± 10.6) for ketorolac vs. 37.2 (± 12.9) for the placebo 
p= 0.007. For the single-dose group, the mean PID scores through 6 hours were 
significantly higher for subjects in the ketorolac group than the placebo group at every 
time point (1/2, 1, 2, 3, 4 hours). Both the peak relief and the maximum PID score prior 
to restarting the PCA were significantly higher in the ketorolac group compared to the 
placebo group. For the single dose regimen, the quality of analgesia was significantly 
better for the ketorolac group compared to the placebo group at ½, 1, 2, 3, 4, and 5 hours 
and approached significance at 6 hours. The duration of analgesia was significantly 
longer in the ketorolac group vs. the placebo group, as denoted by the time to restarting 
PCA or requesting rescue medication (3 vs. 1.3 hours, p < 0.04). A significantly greater 
proportion of patients in the ketorolac group reported meaningful pain relief compared to 
placebo at 1 and 1.5 hours (p< 0.05) and approached statistical significance at 2 hours. 
Morphine use was significantly lower in the ketorolac group compared with the placebo 
group for all time intervals (p< 0.001). The mean (± SE) morphine use for ketorlac vs. 
placebo was 34.0 (±1.64) vs. 48.4 (± 2.93) on day 1, 18.8 (± 11.51) vs. 29.2 (± 2.61) for 
day 2, and 51.4 (± 2.75) vs. 774. (± 5.28) for days 1 and 2. The global pain assessment 
was significantly better for the ketorolac group than the placebo group on days 3 and 4. 
The quality of analgesia rating was significantly higher at the 8 hours in the ketorolac 
group vs. the placebo group at 8 hours: 2.9 (± 0.06) vs. 2.6 (± 0.1), p= 0.011). 
 
Results: Safety 
 

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The rates of adverse events were similar in the two treatment groups (ketorolac 97.5% vs. 
placebo 98.0%) and were characteristic of events observed following major surgery and 
were  not considered related to the study treatment in the majority 80%, (1150/1437) and 
were considered mild (72.9%). In the ketorolac group, nasal irritation (24.1% vs. 1.9%, p 
< 0.0001), throat irritation (7.0% vs. 0.9%) and lacrimation (7% vs. 0%) occurred more 
frequently in the ketorolac group than in the placebo group. Most events related to nasal 
irritation were mild, transient, and did not increase in severity with repeat dosing. Pyrexia 
was reduced in the ketorolac group (44% vs. 67%, P= 0.001). Serious adverse events 
were similar in both groups: 5 patients for ketorolac (2.5%), and 2 patients for placebo 
(1.9%). These were post –procedural hemorrhage (N=2), wound infection (N=1), wound 
complication (N=1), and wound secretion (N=1) for ketorolac and pain (N=1) and 
pleuritic pain (N=1) for placebo. The only serious event rated possibly related to study 
medication was the wound complication. There were no clinically relevant differences 
between the treatment groups regarding vital signs, hematology, or clinical chemistry 
measurements. No deaths occurred during the study.  
 
Conclusion 
 
Intranasal ketorolac was well tolerated and effective in treating moderate to severe 
postoperative pain in inpatients. The convenience of intranasal dosing suggests that its 
usefulness in the ambulatory care setting should be evaluated.  
 
4. Moodie JE, Brown CR, Bisley EJ, Weber HU, Bynum L. The safety and analgesic 
efficacy of intranasal ketorolac in patients with postoperative pain. Anesthesia and 
Analgesia 2008; 107(6): 2025- 2031. 
 
This was a single center, double-blind, randomized controlled study of 127 adult patients 
(N=42 placebo, N= 43 ketorolac 10 mg, N= 42 ketorolac 31.5mg) undergoing major 
surgery. Postoperative patients were randomized to either intranasal administration of 
placebo or ketorolac 10 mg or ketorolac 31.5 mg every 8 hours for 40 hours. The study 
drug was administered intranasally, giving 2 doses of 100 µL of the study drug, with 1 
dose (100 µL to each nostril) via a metered device.  Pain intensity was assessed after 
receiving the study drug. Patient controlled analgesia (PCA) was provided by 
supplemental morphine.  
The subjects rated their pain on a 100 mm visual analogue scale (VAS) where 0= no pain 
and 100 = worst pain possible. The pain intensity difference (PID) was calculated by 
subtracting the post study drug VAS from the baseline (pre-study drug) VAS or PID = 
post- study drug VAS – baseline VAS. The summed PID (SPID) was calculated by 
adding the weighted PID scores over the time intervals.  
 
Outcome measures: The primary outcome measure was the total morphine use by PCA 
pump in the first 24 hours. Secondary outcome measures were total morphine use for first 
2 days (48 hours) and total morphine use on day 2 (24 to 48 hours) 
 
Results: Efficacy 
 

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The analgesic response was significantly greater the for 31.5 mg ketorolac group 
compared with the placebo for day 1, day 2 and the 48-hour morphine use, and for the 4-
hour and 6 hour SPID. The 10 mg ketorolac groups also demonstrated a better analgesic 
response than for the placebo, but the difference was not statistically significant. The 
mean morphine consumption for the 3 groups was day 1 post-op: placebo 56.5 mg, 10 mg 
ketorolac 54.3 and 31.5 mg ketorolac 37.8 mg (p=0.0013), day 2 placebo 32.6 mg, 10 mg 
ketorolac 28.3 mg, and 31.5 mg ketorolac 23.11 mg (p =0.0182), and for the 48 hours 
post-op: placebo 87.9 mg, 10 mg ketorolac 78.7 mg, and 31.5mg ketorolac 61.4 mg (p= 
0.0060). The 4 hour SPID was 75.9, 10 mg ketorolac 89.6, and 31.5 mg ketorolac 120.1 
(p = 0.0017). The 6 hour SPID was placebo 130.6, 10 mg ketorolac 154.8, and 31.5 mg 
ketorolac 195.5 (p=0.0015). 
 
Results: Safety 
 
The frequency of adverse events for the 3 groups was placebo 97.6%, 10 mg ketorolac 
100%, and 31.5 mg ketorolac 95.2%. Most adverse events were mild or moderate. The 
most common adverse events were pyrexia and nausea, both occurring in 50.4% overall. 
Pyrexia was significantly less common (p= 0.0088) in the 31.5 mg ketorolac group than 
in the placebo group, with pyrexia reported in 33.5% of the 31.5 mg ketorolac group, in 
55.8% of the 10 mg ketorolac group and in 61.9% of the placebo group. Tachycardia was 
significantly less frequent in the 31.5 mg ketorolac group than the placebo group (p= 
0.0317). The frequency of tachycardia in the 3 groups was placebo 40.5%, 10 mg 
ketorolac group 16.3%, and 31.5 mg ketorolac group 19.0%, Pruritus was less frequent in 
the ketorolac groups than placebo but the difference was not statistically significant (p= 
0.0790). The frequency of pruritus was placebo 23.8%, 10 mg ketorolac 18.6%, and 31.5 
mg ketorolac 9.5%. Adverse events typically associated with NSAID use (i.e. abdominal 
pain, dyspepsia, hematemesis, fluid retention, and oliguria) were all reported by three or 
fewer subjects in each group. Nasal irritation was reported in the following frequencies: 
placebo 11.9% (5 subjects), 10 mg ketorolac group 14.0% (6 subjects), and 31.5 mg 
ketorolac group 16.7% (7 subjects). The frequency reported for epistaxis was placebo 
2.4% (1 subject), 10 mg ketorolac 2.3% (1 subject), and 31.5 mg ketorolac 7.1% (3 
subjects). All events were mild or moderate in intensity.  
 
Conclusion  
 
Intranasal ketorolac in a 31.5 mg dose demonstrated significant analgesic efficacy 
compared to placebo and 10 mg of ketorolac. 
 
1.3.Risk – Benefit 
 
Ketorolac has value as a medicine to relieve pain. Ketorolac has numerous advantages 
over other classes of analgesics, especially opioids. Since ketorolac does not bind to 
opiate receptors, it is nonaddicting and avoids the side effects of the opioids.3 Therefore, 
some of the advantages include: lesser incidence of respiratory depression, lesser 
incidence of hypotension, lesser incidence of constipation, and no danger of addiction. 
Multiple studies have demonstrated the benefit of ketorolac as a medication to decrease 

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14
or eliminate pain. Ketorolac has been proven effective for pain relief, especially for 
certain types of pain; such as musculoskeletal pain, headaches and the pain from renal 
colic. In appropriate patients; ketorolac is a relatively safe drug for the treatment of 
pain.4-6 Side effects and complications, such as gastrointestinal complaints (e.g. 
abdominal pain, dyspepsia, GI bleeding) and renal dysfunction (elevation of the BUN and 
creatinine) have been reported but with appropriate patient selection are uncommon or 
rare. The use of NSAIDS including ketorolac is not recommended in patients with active 
peptic ulcer disease, renal disease or at risk for renal failure due to volume depletion, 
cerebrovascular bleeding, hemorrhagic disorders, or those with a high risk of bleeding. 
With appropriate patient selection, ketorolac can be a safe and effective medication for 
the relief of pain. 
 
3.  
Highlights of prescribing information.  Distributed by American Reagant, Inc. 
Shirley, NY 1967. 
4.         Rainer TH, Jacobs P, Ng YC, et al. Cost-effectiveness analysis of intravenous 
ketorolac and morphine for treating pain after limb injury: double-blind, 
randomized controlled trial. BMJ 2000; 321:1247-1251. 
5. 
 Cordell WH.  Renal (ureteral) colic. In: Mace SE, Ducharme J, Murphy MF 
(eds). Pain management and Sedation: Emergency Department Management. 1st 
ed. New York: McGraw-Hill Co, 2006; Ch. 36, pp. 261- 268.3. 
6.  
Kelly A. Headaches. In: Mace SE, Ducharme J, Murphy MF (eds). Pain 
management and Sedation: Emergency Department Management. 1st ed. New 
York: McGraw-Hill Co, 2006; Ch. 38, pp. 261- 268.3, pp.279-285. 
 
2. STUDY OBJECTIVES AND ENDPOINTS  
 
2.1 Objectives 
2.1.1 Primary Objective 
To determine the efficacy of intranasal ketorolac (sprix) in decreasing the acute pain of 
patients in the emergency department (ED) 
 
2.1.2 Secondary Objective 
To determine the safety and tolerability of intranasal ketorolac (sprix) in decreasing the 
acute pain of patients in the emergency department (ED) 
 
2.2 Variables 
2.2.1. Primary Efficacy Variable 
The primary efficacy variables are the pain measurements after the administration of the 
intranasal ketorolac (sprix) as compared with the baseline pain scales. Pain scales to be 
used are the Numeric Rating Scale (NRS) where 0 = no pain and 100 mm = worst pain 
possible and the global assessment of pain (using a 5 point Likert scale) and the global 
assessment of analgesia (pain relief) (using a 5 point Likert scale) (See appendix 1) 
2.2.2 Secondary Efficacy Variable 
The secondary efficacy variables are additional (calculated) pain measurements after the 
administration of the intranasal ketorolac (sprix). This will include the pain intensity 
difference (PID) and the summed pain intensity difference (SPID) (See appendix 1) 

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2.2.3 Safety Variables 
2.2.3.1 Primary Safety Variables 
The primary safety variables are the occurrence of adverse events (after the intranasal 
ketorolac has been administered) 
2.2.3..2 Secondary Safety Variables  
The secondary safety variables are the vital signs taken after the intranasal ketorolac has 
been administered. An additional secondary safety variable is the appearance of the nasal 
mucosa after the administration of the intranasal ketorolac, sprix. 
 
3.  
INVESTIGATIONAL PLAN 
 
3.1 
Overall Study Design and Plan 
 
This is a prospective, nonblinded, efficacy, safety and tolerability trial in non-geriatric 
adults (from age 18 to 64 years) who are in the emergency department (ED) being treated 
for moderate to severe acute pain (e.g. NRS ≥ 4 on a 0 to 10 NRS or ≥ 40 on a 0 to 100 
NRS). Written consent is obtained from the patient. Eligible subjects will be enrolled.  
 
3.2  
Study Population 
 
3.2.1 Description 
 
Adult non-geriatric (ages 18 to 64 years) subjects who present to the emergency 
department (ED) in moderate to moderately severe acute pain (e.g. NRS ≥ 4 on a 0 to 10 
NRS or ≥ 40 on a 0 to 100 NRS) from an acute illness or injury (such as a kidney stone or 
an acute musculoskeletal injury) are eligible for enrollment in the study 
 
3.2.2 Inclusion Criteria 
 
A patient is eligible for enrollment into the study if all of the following criteria (and none 
of the exclusion criteria) are met: 
 
1. 
Patient is being seen in the emergency department (ED) in acute pain from 
an acute illness or injury (such as a kidney stone or an acute  
musculoskeletal injury) 
2. 
Age ≥ 18 years and < 65 years 
3. 
Stable patient with stable vital signs, including not in shock (systolic BP 
>90), not in respiratory failure, and not a multiple trauma patient 
4. 
Mentally competent patient is able to understand the consent form 
5. 
Baseline pain score is moderate to severe (e.g. on NRS ≥ 4 on a 0 to 10 
NRS or ≥ 40 on a 0 to 100 NRS) 
 
3.2.3. Exclusion Criteria 
 
A subject will be excluded from the study if any of the following criteria are met: 
 

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1. 
Unstable patients 
2. 
Multiple trauma patients 
3. 
Patients with any allergies to ketorolac or any of the components in the 
nasal spray preparation 
4. 
Patients with active peptic ulcer disease 
5. 
Patients with a history of asthma, urticaria, or other allergic-type reactions 
after taking aspirin or other NSAIDS 
6. 
Patients about to undergo major surgery 
7. 
Patients with renal disease or at risk for renal failure due to volume 
depletion 
8. 
Pregnant or nursing mothers 
9. 
Patients with suspected or confirmed cerebrovascular bleeding, patients 
with hemorrhagic diathesis, incomplete hemostatis, and those at high-risk 
of bleeding 
10. 
Patient with a nasal abnormality or illness that could affect the absorption 
of intranasal medication (such as: nasal discharge, rhinitis, acute upper 
respiratory infection, acute epistaxis, nasal polyp, nasal tumor) 
11. 
Patient with any other contraindication to the use of Sprix, or in whom use 
of Sprix would not be consistent with the approved package insert 
 
 
3.3 Rationale for Choice of Study Design and Population 
 
This is a prospective efficacy, safety and tolerability trial in non-geriatric adults. Active 
treatment (a single dose of intranasal ketorolac) will be used. The population selected for 
this study, adult nongeriatric patients is a patient population that may benefit from the use 
of intranasal ketorolac. This is a population in whom intranasal ketorolac has been 
approved for use and in whom intranasal ketorolac has been shown to be safe and 
effective when used for other types of pain, specifically post-operative pain from major 
surgery and post-operative dental surgery. This is also a population in whom, other routes 
of administration of ketorolac, (e.g. intravenous, intramuscular and oral) have been 
shown to be efficacious and safe.  Therefore, it seems highly likely that the intranasal 
form of ketorolac, in an appropriate dose of 30 mg will also be effective, safe and well 
tolerated.  
 
 
4. STUDY TREATMENTS 
 
4.1 Medication(s) for study treatment. 
The following study treatments will be administered in this study: 
Ketorolac Tromethamine (Sprix) Nasal Spray 
Manufactured by Luitpold Pharmaceuticals  
 
Subjects in the emergency department with acute pain will be administered a single dose 
of intranasal ketorolac as per standard application (see 4.2). 
 

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4.2 Method for Application of Ketorolac (Sprix) for the Treatment of Acute Pain 
 
After identifying appropriate adult patients (see section 3.2), obtaining written consent 
(see section 9.3), and performing all pre-dose (baseline) pain assessments, ketorolac 
(Sprix) will be administered in the standard fashion. 
 
A single dose of 31.5 mg will be administered with one 15.75 mg spray (in a metered 
dose of 100 µL per spray) in each nostril for a total of two intranasal sprays per patient 
that total 31.5 mg in 200 µL. Note: The time at which the second intranasal spray 
administration is completed is time 0.  As stated above, the baseline pain assessments will 
be completed prior to the administration of the intranasal ketorolac (sprix). 
 
4.3 Storage, Handling, and Administration 
 
Current ICH GCP Guidelines requires the study investigator to ensure that study 
treatment (e.g. nasal spray bottles of sprix) deliveries from the Sponsor are received by a 
responsible person (e.g. research designee or pharmacist), and also ensure: 
                  
 The deliveries are recorded.  
 
 The study treatment is handled and stored safely and properly. 
 
 The study treatment is only dispensed to study subjects in accordance with the 
protocol. 
 
The study treatment, intranasal ketorolac (sprix), will be stored in accordance to product 
labeling. Exposure to light, freezing and extreme heat should be avoided. It is 
recommended that the study treatments (e.g. unopened sprix) be stored between 36° F 
and 46°F (2°C and 8°C). During use, containers of Sprix Nasal Spray  will be kept at 
controlled room temperature between 59°F and 86°F (15°C and  30°C), and out of direct 
sunlight. In this study, once a subject has received the intranasal ketorolac (sprix) spray, 
the bottle will be discarded. Each subject will receive the recommended dose of sprix 
(31.5 mg with one 15.75 mg spray in a metered dose of 100 µL per spray in each nostril 
for a total of two intranasal sprays [total of 200 µL] per patient from a new previously 
unused intranasal bottle of sprix. There will be only one use per bottle of sprix or one 
bottle of sprix per subject and there will be no other uses from the same intranasal spray 
bottle. Each patient will receive a single dose of intranasal ketorolac. 
 
The study treatment (e.g. intranasal ketorolac or sprix) will be checked for expiration 
dates prior to use to ensure that expired product will not be used. 
 
Study treatment inventory and accountability records will be kept by the study 
investigator or designee. Accountability will be documented throughout the study. The 
procedures below are mandatory: 
    

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The Investigator will not supply any study treatment to subject’s not enrolled ion the 
study. 
 
The research designee or pharmacist will store the study treatment (e.g. intranasal 
ketorolac: sprix) in a secure storage facility under controlled storage conditions, 
accessible only to persons authorized by the Investigator to dispense study treatment. 
 
The research designee or pharmacist will maintain study inventory. The inventory will 
include a detailed accounting of materials received and dispensed to each subject. 
 
At the conclusion of the study, a final study treatment inventory on the Treatment 
Accountability Log will be conducted and the results of this inventory will be recorded. It 
must be possible to reconcile delivery records with those of used and unused study 
treatment. 
 
4.4 Packaging and Labeling  
 
Intranasal ketorlac (sprix) is packaged in a nasal spray bottle that delivers a mist 
containing 15.75 mg in a metered dose of 100 µL per spray administered in each nostril 
for a total of two intranasal sprays per patient with 31.5 mg total drug administered per 
dose. 
 
4.5 Study Treatment Accountability 
 
The study investigator/designee will verify that study treatments are received intact and 
in the correct amounts. This verification will be documented by signing and dating the 
Treatment Accountability Log. An accurate running inventory of the study treatment will 
be kept by the Investigator /designee, and will include the type of study treatment and the 
date the study treatment was dispensed. 
 
4.6 Treatment Compliance  
 
The prescribing information for each study treatment of intranasal ketorolac (sprix) and 
any other treatments (including medication(s), dose(s), route, and time(s) administered) 
by any route of administration (intravenous, intramuscular, oral, etc.) ordered by the 
clinician, (such as: other pain medications, sedatives, etc.) will be recorded.  
 
5.  SCHEDULE AND DESCRIPTION OF STUDY PROCEDURES 
 
Study procedures will be performed as outlined in Figure 1 and summarized in Part 3: 
Investigational Plan. 
 
Signed informed consent must be obtained from the subject before any study-related 
procedures may be performed. 
Details regarding the informed consent process are provided in Section 9.3. 
 

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5.1 Study Procedures 
 
5.1.1 Pre-Study Period 
 
5.1.1.1 Present to the Clinical Site 
 
Adult (non-geriatric) subjects ages 18 to 64 years with an acute painful injury or illness 
(such as an acute isolated musculoskeletal injury or a kidney stone) being seen in the 
emergency department may be eligible for this study. 
 
5.1.2 Informed Consent 
 
The patient will be approached to determine his/her interest in this study. If a subject is 
interested in the study, written informed consent is obtained (section 9.3) and screening 
will begin. 
 
5.1.3. Patient Screening and Subject Log 
 
After the patient presents to the clinical site, the Investigator/designee may review the 
patient’s charts. A unique screening number will be assigned to patients that have had 
their records reviewed. This screening number will be assigned according to the 
institution’s policies and procedures and may not contain any information that may assist 
in identifying the patient. A Subject Log will be maintained by the research site.  
 
5.1.3.1 Screening Assessments 
 
The following screening assessments will be completed during screening and the findings 
will be recorded. 
 
۰ Inclusion and exclusion criteria (Sections 3.2.2 and 3.2.3, respectively) 
 
۰ Patient number assigned 
 
۰ Demographic information 
 
5.1.4 Study Treatment 
 
Study treatment assessments will be performed during the time the patient is in the 
clinical site and will be performed, if indicated at specific times (see subsections below)  
The following information will be obtained and the findings will be recorded: 
 
Study treatment assessments at specified times (baseline prior to administration and after 
administration of intranasal ketorolac [sprix]) including vital signs (baseline, before 
administration of intranasal ketorolac) and after administration of intranasal ketorolac 
(prior to the patient leaving the clinical site, e.g. emergency department). 
 

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 Pain assessments  
 Patient/health care provider questionnaires will be done prior to the patient 
leaving the clinical site   
 Any side effects/adverse events 
 Vital signs 
 
5.1.4.1 Site Assessment 
 
Pre/Post Administration of Intranasal Ketorolac (Sprix): The Healthcare provider will 
examine the patient’s nasal mucosa and document the findings (such as: redness, 
drainage) both before administration and after administration of the intranasal ketorolac 
(sprix). Note: Any subject with abnormalities of the nasal passageway such as purulent 
discharge or epistaxis will be excluded from participation in the study. 
 
5.1.4.2 Study Pain Assessments  
 
Study pain assessments will be done before and after the administration of the single dose 
of intranasal ketorolac (sprix). All patients will have a minimum of two pain scores 
(NRS): a baseline (pre administration of the intranasal ketorolac) and a post 
administration of intranasal ketorolac. The time that the pain score is done, whether at 
baseline or post intranasal administration of the ketorolac, will be recorded any time a 
baseline or post-treatment NRS pain score is done. A post-treatment NRS pain score will 
be done immediately prior to the patient leaving the ED and immediately prior to the 
patient receiving rescue medication (e.g. any additional pain medication or sedatives) 
with the time post-treatment to be recorded. Depending on the length of time the patient 
is in the ED, additional NRS pain sores will be done, if possible. While the patient is in 
the ED, additional NRS pain scores will be recorded at specified times after study drug 
administration; specifically, at 20 minutes, 40 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 
5 hours and 6 hours for as long as the patient remains in the clinical site, in addition to 
time 0 (baseline = before administration of the study drug).  (See Appendix 1) The pain 
scores will be compared and analyzed for statistical significance comparing the baseline 
(pre-study drug administration) with the “post-study drug administration or “treatment” 
pain scores. 
 
5.1.4.3 Study Questionnaires 
 
Study Questionnaires will be done by the patient and the health care provider after 
administration of the study drug (intranasal ketorolac [sprix]), prior to the patient leaving 
the clinical site. (See Appendix 2) 
 
5.1.4.4. Standard-of-Care Procedures: Pain Management 
 
Patients may receive additional medications as part of their emergency department 
treatment including additional pain medications, such as opioids. Any additional 
medications administered will be recorded. The need for additional medications 
(including the drug administered, the dose, the time, and the route of administration) will 

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be recorded. The need for additional pain medications (or the lack of need for additional 
pain medications) may also be a secondary efficacy endpoint.  
 
5.1.5 Description and Documentation of Study Procedures  
 
5.1.5.1 Study Number 
 
The subject will be assigned a study number. This will be recorded in a study log. This 
will maintain patient confidentiality and eliminate patient identifiers from the patient case 
report form. 
 
5.1.5.2 Demographics 
 
The subject’s age, gender, race/ethnicity, will be recorded.  
 
5.1.5.3 Medical History 
 
Relevant medical history for each subject will be obtained in order to determine 
eligibility in the study. Eligibility will be noted. 
 
5.1.5.3 Medications during the Study 
 
All medications administered in the emergency department (drug name, dose, route and 
time of administration) including the study drug and additional pain medications will be 
recorded.  
 
5.1.5.4 Intranasal Ketorolac (Sprix) Administration during the Study 
 
Intranasal Ketorolac (Sprix) will be administered in the standard manner as per the 
protocol and manufacturer instructions. 
 
5.1.6 Efficacy Assessments 
 
5.1.6.1 Pain Assessments 
 
Pain scores will be recorded and documented before administration of the intranasal 
ketorolac (sprix) for a baseline pain assessment and at specified intervals after the 
administration of intranasal ketorolac (sprix). Post-treatment pain scores will be recorded 
immediately prior to discharge from the ED and immediately prior to any rescue (e.g. 
pain or sedative) medication. Post treatment pain scores will be collected for as long as 
the patient is in the clinical site and will be at 20 minutes, 40 minutes, 1 hour and for 1 
hour intervals post treatment up to 6 hours (e.g. at 1, 2, 3, 4, 5, and 6 hours) in addition to 
pain scores immediately prior to rescue medication and immediately prior to discharge 
from the ED. Pain assessments will be by the Numeric Rating Scale (NRS).where 0 = no 
pain and 100 = the worst pain imaginable. (See Appendix 1) 
 

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5.1.6.2. Patient Questionnaires 
 
Patient questionnaires will be obtained after administration of the intranasal ketorolac 
(sprix) and prior to the patient leaving the clinical site. (See Appendix 2) 
 
5.1.6.3 Health Care Provider‘s Questionnaire(s) 
 
The health care provider questionnaires will be obtained after administration of the 
intranasal ketorolac (sprix) and prior to the patient leaving the clinical site. (See 
Appendix 2) 
 
5.1.6.4 Safety Assessments 
 
5.1.6.5 Site Assessments: Clinical 
 
Site assessments (clinical) of the nasal passageways e.g. an examination of both nostrils) 
will be done before and after administration of the intranasal ketorolac (sprix). This will 
document that there is no changes in the nasal mucosa, etc. secondary to the 
administration of the intranasal drug (sprix). 
 
5.1.6.6 Side Effects/Adverse Events  
 
Any and all side effects/adverse effects will be documented on the case report form. The 
health care provider will determine whether the side effect/adverse event is or is not 
related to the intranasal ketorolac (sprix). 
 
5.2 Protocol Deviations 
 
No deviations to the inclusion/exclusion criteria are allowed in this study. All deviations 
will be recorded on the patient’s chart and on the appropriate case report form. 
 
5.3 Study Withdrawal Criteria 
 
5.4 Discontinuation of Study Treatment/Early Release from the Study 
 
A subject who is enrolled in the study and for whom study treatment is prematurely 
terminated will be considered to be discontinued from study treatment. After 
discontinuation/early release from the study, the subject will receive standard-of-care 
treatment as per the treating clinician. End of Study Efficacy and Safety assessments  
will be performed, if appropriate and whenever possible. 
 
5.5 Withdrawal for the Study 
 
A subject may be withdrawn from the study at any time for any reason and without 
penalty or prejudice. The following situations may be cause for a subject to be withdrawn 
from the study: 

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 Subject did not fulfill the inclusion or exclusion criteria. 
 Subject experienced a significant complication, deemed due to the study treatment 
 Subject developed an intercurrent illness, condition, or procedural complication 
that would interfere with continued participation 
 Subject voluntarily withdrew consent/ authorization 
 Subject was in violation of the protocol 
 Treating health care provider (e.g. physician or mid-level provider) deemed it in 
the best medical interest of the subject to terminate involvement in the study at 
any time 
 
Upon occurrence of a serious adverse event or intolerable adverse event, the principal 
investigator will be notified. If a subject is discontinued from study treatment due to a 
serious adverse event, the event will be followed until resolution. The investigational 
staff will record on the case report form the reason(s) for discontinuation.  
 
5.6 Noncompliance/Replacement 
  
Subjects who discontinue from the study prematurely will not be replaced. 
 
6.  DEFINITIONS AND DESCRIPTIONS OF ASSESSMENTS AND ENDPOINTS 
 
6.1 Pharmacokinetic/Pharmacodynamic Endpoints and Assessments 
 
No pharnmacokinetic/pharmacodynamic endpoints or assessments will be performed in 
this study. 
 
6.2 Efficacy Variables 
 
6.2.1 Primary Efficacy Variable 
 
 The primary efficacy variable is the assessment of pain by the NRS after the 
administration of intranasal ketorlac (sprix). 
 
6.2.2 Secondary Efficacy Variables 
 
The secondary efficacy variables are the global pain assessment scores, the global 
assessment of analgesia (pain relief) scores, the patient questionnaire and the health care 
provider questionnaire which are completed before the patient leaves the clinical site (e.g. 
ED). 
 
6.3 Safety Variables 
 
6.3.1 Primary Safety Variable  
 

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The primary safety variables are the occurrence of adverse events (after the intranasal 
ketorolac has been administered). 
 
6.3.2 Secondary Safety Variables  
 
      The secondary safety variables are the vital signs taken after the intranasal ketorolac has 
been administered. An additional secondary safety variable is the appearance of the nasal 
mucosa after the administration of the intranasal ketorolac and prior to the patient leaving 
the clinical site. The nasal mucosa (both sides) will be examined for any abnormalities 
such as erythema, discoloration, swelling, etc at baseline (prior to administration of the 
intranasal study drug, sprix), and after administration of the intranasal study drug, sprix). 
 
 
 
6.3.3 Adverse Events 
 
6.3.3.1 Definitions 
 
An adverse event is defined as any untoward medical occurrence in a subject 
administered a study treatment and which did not necessarily have a causal relationship 
with the treatment. An adverse event could therefore, be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a study treatment, 
whether or not related to the study treatment. 
 
For the purposes of this study, a treatment-emergent adverse event is defined as any 
adverse event that occurs during the emergency department visit and after administration 
of the intranasal ketorolac (sprix). The treating clinician should reflect whether the event 
was considered to be “possibly related” or “not related” to any protocol mandated 
procedures during the study. 
 
6.3.3.2 Serious Adverse Event 
  
A serious adverse event is any untoward medical occurrence that: 
 
 Results in death 
 Is life-threatening 
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly or birth defect, or 
 Requires non-illness or injury related (presenting condition) inpatient 
hospitalization or prolongation of existing hospitalization (hospitalization for 
treatment /observation/examination caused by an adverse event is considered to 
be a serious adverse event) 
 
Important Medical Events: 
 
Important Medical Events are defined as events that:  

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 may not result in death 
 may not be life-threatening 
 may not require hospitalization  
 
These may be considered serious adverse, based upon appropriate medical judgment. 
These events may jeopardize the patient or subject and may require surgical intervention 
to prevent one of the outcomes listed in this definition (21 CFR 312.32) 
 
6.3.3.3 Reporting 
 
Any serious, adverse event will be reported immediately to the Institutional Review 
Board. 
 
7. DATA ANALYSIS AND STATISTICAL METHODOLOGY 
 
7.1 Planned Sample Size 
 
Since this is a prospective, efficacy and safety trial, the planned enrollment is for 25 
patients who will receive a single dose of intranasal ketorolac. This sample size provides 
80% power to demonstrate that the mean pain intensity to demonstrate that the mean pain 
intensity difference (PID), (where the PID = post-treatment NRS – baseline NRS) differs 
from zero when the effect size is 0.56. The effect size was calculated as the mean PID 
divided by the standard deviation. 
 
7.2 Efficacy 
 
The pain scores pre and post-treatment (after administration of the intranasal ketorolac 
[sprix] will be compared. Pain scales are a continuous variable. Therefore, pain scales 
and other pain assessments (such as PID, SPID) (all continuous variables) will be 
compared using t-test or F-test. 
The questionnaires (patient and health care provider) are discrete variables and will be 
compared using chi-square or Fischer’s exact test. 
Significance is at p= 0.05. 
 
7.3 Safety 
 
 Safety will be assessed by adverse events documented on the case report form. 
 Safety will be assessed by clinical assessment including vital signs before and 
after administration of the study drug, intranasal ketorolac (sprix). 
 Safety will also be assessed by clinical assessment of the nasal mucosa before 
and after administration of the study drug, intranasal ketorolac (sprix). 
       
8. TERMINATION OF THE STUDY 
 

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The study will be terminated when 25 subjects are enrolled and all data is obtained and 
documented on the case report form. A statistical analysis will follow, an abstract for 
presentation will be submitted and a manuscript for publication in a peer reviewed 
medical journal will be written. 
 
9. ADMINISTRATION AND REGULATORY CONSIDERATIONS 
 
9.1 Prior to Initiation of the Study 
 
All regulatory requirements prior to initiation of the study must be met. This includes 
institutional review board approval (see 9.2) 
 
9.2 Institutional Review Board 
 
Appropriate documentation will be submitted to the Cleveland Clinic Institutional 
Review Board. Written and electronic approval will be obtained from the Cleveland 
Clinic Institutional Review Board prior to initiating the study. 
 
9.3 Informed Consent/Authorization 
 
The appropriate Consent forms will be approved by the Cleveland Clinic Institutional 
Review Board prior to initiating the study. 
 
9.4 Duties of the Investigator 
 
The study investigator will comply with the requirements for human investigation as set 
forth by the Cleveland Clinic Review Board. 
 
9.5 Monitoring 
 
Monitoring and auditing by the Cleveland Clinic Institutional Review Board and other 
relevant regulatory authorities may occur.  The confidentiality of the subject’s identity 
will be protected according to regulations when source documents are accessed. 
 
9.6 Study Records 
 
 Inclusion and exclusion criteria information 
 Participation in the study (signed and dated informed consent/authorization) 
 Visit date 
 Efficacy and safety data 
 Adverse events, if any 
 Premature discontinuation rationale, if applicable 
 Completion or termination of the study  
 
9.7 Records Retention   
 

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Appropriate records will be kept as per the Cleveland Clinic Institutional Review Board 

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9.8 Subject Privacy/Authorization  
 
Subject information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Medical information may be assessed only after 
approval from the subject to the Investigator or to other appropriate medical personnel 
responsible for the subject’s well being. The Sponsor will not disclose any confidential 
information regarding subjects during performance of study duties without justifiable 
reasons. The sponsor affirms the subject’s right to protection against invasion of privacy. 
Only subject identification numbers and /or initials will identify subject data; however, 
the IRB, and regulatory authorities may have direct access to any study- related 
information. The HIPAA and PIPEDA Privacy Rule provides federal protection for the 
privacy of protected health information (PHI) by implementing standards to protect and 
guard against the misuse of individually identifiable health information of subjects 
participating in sponsored clinical trials. “Authorization’’ is required from each subject 
participating in this study (i.e. specific permission granted by an individual to a covered 
entity for the use and disclosure of an individual’s PHI). A valid authorization must meet 
the implementation specifications under the HIPPA/PIPEDA Privacy Rule. A valid 
authorization is available at the Cleveland Clinic.  
 
 
LIST OF FIGURES 
 
Figure 1:  
 
Schematic Representation of Study Design 
 
 
APPENDIX 
 
Appendix 1A:  
Numeric Pain Rating Scale 
Appendix 1B:  
Global Pain Assessment Scale 
Appendix 1C:            Global Assessment of Analgesia   
                                    (Global Assessment of Pain Relief) 
Appendix 1D:            Calculated Pain Assessments  
 Appendix 2:   
Questionnaires 
Appendix 2A:  
Patient Questionnaire 
Appendix 2B:  
Health Care Provider Questionnaire 
 
 
 
 
 
 
 
 
 

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Figure 1: Schematic Representation of Study Design 
 
 
Identification of Patient in the Emergency Department 
 
Patient Screening  
 
Patient Meets Enrollment 
 
Written Consent Obtained 
 
Baseline Study Data Obtained (includes pretreatment pain scales and vital signs) 
 
Health Care Provider (RN) Administers Intranasal Ketorolac 
 
Record Time to Patient’s Onset of Analgesia (First Perceptible Pain Relief (in minutes))  
(Patient informs nurse) 
 
Record Time to Patient’s First Meaningful Pain Relief (in minutes)  
(Defined as “relief that definitely makes you feel better”) 
(Patient informs nurse) 
 
Post-treatment Assessment (includes post-treatment pain scales immediately prior to the 
patient’s discharge from the Ed and immediately prior to rescue medication and if 
possible depending on the length of the patient’s ED stay at specific times: 20 minutes, 
40 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours for as long as the patient 
remains in the clinical site)  
 
Post-treatment Assessment Vital Signs 
 
Documentation of any Adverse Events/Side Effects (with determination by the treating 
physician whether the side effect/adverse event is related to the study drug) 
 
Patient/Healthcare Providers (RN, treating MD) Questionnaires Completed 
 
 
 
 
 
 
 
 
 
 

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Appendix 1A: Numeric Pain Rating Scale 
 
 
                Numeric Rating Scale 
 
 
 
 
 
      No Pain                             Moderate Pain                                Worst pain 
           |------|------|------|------|------|------|------|------|------|------| 
 
            0     10     20     30     40     50     60    70     80     90    100 
 
 
 
 
 
 
 
 

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Appendix 1B: Global Pain Assessment Scale 
 
How would you rate your pain? 
0 = none 1 = a little (mild) 2 = some (moderate) 3 = severe  
4 = very severe (extreme)  
 
Appendix 1C: Global Assessment of Analgesia   
                        (Global Assessment of Pain Relief) 
How would you rate your pain relief? 
0 = poor   1= fair   2= good   3 = very good   4 = excellent 
 
Appendix 1D: Calculated Pain Assessments: 
                         Pain Intensity Difference (PID) 
                         Summed Pain Intensity Difference (SPID) 
                         (Weighted Sum of PID) 
                         Total Pain Assessment Relief (TOTPAR)   
                         (Weighted sum of pain relief scores) 
 
Appendix 2:Questionnaires 
 
Appendix 2A: Patient Questionnaire 
 
1. 
Did the intranasal pain medicine decrease your pain? yes________ no_________ 
2. 
How effective was the intranasal pain medicine in decreasing your pain? 
Mild decrease in pain__   Moderate decrease in pain___ Strong decrease in 
pain____ 
3. 
 How satisfied were you with the use of the intranasal spray?  
Very unsatisfied__ Unsatisfied____ Satisfied___ Very satisfied_____ 
4. 
Would you consider using this intranasal pain medicine in the future when you 
had pain? yes____ no_____ 
 
Appendix 2B:  
Health Care Provider Questionnaire 
 
1.  
Was the patient successfully treated (had less pain) by using the spray?  
yes___ no___ 
2   
 Did the patient have any unacceptable side effects from use of the spray? 
yes__no___. 
3.  
How satisfied How satisfied were you with the use of the intranasal spray?  
Very unsatisfied__ Unsatisfied____ Satisfied___ Very satisfied____  
4.  
Would you consider using this intranasal pain medicine in the future for your 
patients who have acute pain? yes____ no_____ 
 
 
 
              
 

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