Safety and Efficacy of Multiple Doses of Ketorolac Tromethamine Administered Intranasally for Postoperative Pain

Study Overview
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Brief Summary
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This was a randomized, double-blind, placebo-controlled study in subjects who underwent major surgery. Each subject's study participation consisted of a screening visit and a treatment period of up to 5 days. Following surgery (Day 0), subjects were randomly assigned to receive intranasal ketorolac 30 mg or intranasal placebo when the pain intensity (PI) rating equaled at least 40 mm on a 100-mm visual analog scale (VAS). Subjects received study drug every 8 hours for 48 hours and then 3 times daily for up to 5 calendar days in total; the frequency of dosing could be reduced after 48 hours. Starting at the time of the first dose of study drug and continuing for the first 48 hours after surgery, the subjects had access to morphine sulfate (MS) administered via patient controlled analgesia (PCA). After PCA was no longer required, backup pain relief was provided by another standard nonsteroidal anti-inflammatory drug (non-NSAID) analgesic regimen. If the subjects were discharged before postoperative Day 4, they could self-medicate at home through postoperative Day 4. A safety follow-up evaluation was conducted by telephone approximately 14 days after the end of dosing in a subset of subjects (n = 60). The primary objective was to evaluate the analgesic efficacy of multiple intranasal doses of ketorolac administered for up to 5 days. The secondary objective was to evaluate the safety and tolerability of this dosing regimen.

Official Title
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A Phase 3, Double-blind, Randomized Study of the Safety, Tolerability, and Analgesic Efficacy of Multiple Doses of Ketorolac Tromethamine Administered Intranasally for Postoperative Pain

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Ketorolac tromethamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women, age 18 years or older. Body weight > or = to 100 pounds and < or = to 300 pounds. Women of childbearing potential must have a negative serum pregnancy test result. Able to provide written informed consent. At least moderate pain as determined by a PI score of > or = to 40 mm on a 100-mm VAS. Expected to remain in the hospital for at least 48 hours with the possibility of remaining for 5 days. Willing and able to comply with all testing and requirements defined in the protocol. Willing and able to complete the post-treatment visit. Exclusion Criteria: Allergy or sensitivity to ketorolac or EDTA. Allergic reaction to aspirin or other NSAIDs. Current upper respiratory tract infection or other respiratory tract condition that could interfere with the absorption of the nasal spray or with the assessment of adverse events. Use of any intranasal (IN) product within 24 hours prior to study entry. Clinically significant abnormality on screening laboratory tests. History of cocaine use resulting in nasal mucosal damage. Active peptic ulcer disease, recent (defined as within 6 months) history of peptic ulcer disease or gastrointestinal bleeding considered by the investigator to be clinically significant. Advanced renal impairment (serum creatinine > 1.5 mg/dL) or a risk for renal failure due to volume depletion. A history of any other clinically significant medical problem, which in the opinion of the investigator would interfere with study participation. Participation within 30 days of study entry or within 5 times the half- life, whichever is longer, in another investigational drug study. Allergy or significant reaction to opioids. Pregnancy or breastfeeding. Previous participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketorolac tromethamine<br> | Drug: Ketorolac tromethamine<br>* 30 mg intranasal post-surgery for up to 5 days total<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Intranasal post-surgery for up to 5 days total<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Summed Pain Intensity Difference (SPID) on Day 1 | Ratings of Pain Intensity (PI) were made using a 100-mm Visual Analog Scale (VAS) on which 0 = no pain and 100 = worst pain possible. The PI values were obtained every hour following the first dose of study medication on Day 1. Pain intensity difference (PID) was calculated by subtracting the posttreatment score from the baseline score, where the baseline score was the PI rating made prior to the first dose of study medication. A summed PID (SPID) on the first postoperative day was calculated at 6 hours. | 6 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphine sulfate consumption at 24 hours and 48 hours |  | 24 hours and 48 hours after drug administration | 
| Hourly Pain Intensity Difference (PID) scores. | Ratings of Pain Intensity (PI) were made using a 100-mm Visual Analog Scale (VAS) on which 0 = no pain and 100 = worst pain possible. The PI values were obtained during the first 8 hours following the first dose of study medication on Day 1. PID was calculated by subtracting the posttreatment score from the baseline score, where the baseline score was the PI rating made prior to the first dose of study medication. | Hourly following the first dose of study medication up to 8 hours | 
| Quality of analgesia | Quality of analgesia was assessed on a 5-point categorical scale with 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. | First dose of study medication on Day 1 to the first dose of MS by PCA | 
| Global assessment of pain control | A global evaluation of pain control was conducted once daily at bedtime using a 5-point categorical scale on which 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. | 8 hours following first dose of study medication | 
| Onset and duration of pain relief | The onset of pain relief was defined as the time when the stopwatch was stopped to indicate meaningful pain relief. Peak PID was calculated. Duration of analgesia was defined as the time from the first dose of study medication on Day 1 to the first dose of MS by PCA. | 8 hours following first dose of study medication |