Safety and Efficacy of Multiple Doses of Intranasal Ketorolac in Postoperative Pain Following Major Abdominal Surgery

Study Overview
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Brief Summary
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Ketorolac has been marketed for several years in other forms (tablet and injectable) for the short-term relief of pain. This study will test whether a new dosage form (nasal spray) containing ketorolac is effective at relieving the pain of major abdominal surgery, and will also assess product safety. Previous studies with the nasal spray have suggested that it is similar to the previously approved injectable form in effectiveness for pain relief and in its safety profile. Patients will be randomized in a 2:1 ratio to receive intranasal ketorolac or placebo when the pain reaches a moderate level (40 on a scale of 100) following surgery. After the first dose, subjects will receive study drug every 6 hours for 48 hours, and then as needed (up to 4 times a day) for a total of 5 days. If pain is not adequately relieved by the study drug, subjects will be given morphine sulfate or other standard analgesics. Follow-up safety evaluations will occur about 1 and 2 weeks after the start of dosing. Subjects will be asked to answer questions about their pain relief and any possible side effects of the drug during the study, and will be given physical examinations, including nasal evaluations, before and during the clinical trial. A small amount of blood will be drawn for routine clinical laboratory testing.

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 Following Major Abdominal Surgery

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Intranasal Ketorolac Tromethamine
* Drug: Intranasal Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women age 18 through 64 years Major abdominal surgery Body weight ≥ 100 and ≤ 300 pounds Negative serum pregnancy test Pain intensity score at least 40 (moderate pain) on 100 mm visual analog scale Minimum 48 hour hospital stay and 5 day maximum stay Able to provide written informed consent Willing and able to comply with all testing requirements of the protocol Exclusion Criteria: Allergy or sensitivity to ketorolac or ethylene diamine tetraacetic acid (EDTA) Allergy or significant reaction to opioids Allergic reaction to aspirin or other nonsteroidal anti-inflammatory drug (NSAIDs) Current upper respiratory tract infection or other respiratory tract condition that could interfere with absorption of the nasal spray or adverse event assessment Use of any intranasal product in past 24 hours Clinically significant abnormality on screening lab tests History of cocaine use Active peptic ulcer disease or significant history of peptic ulcer disease or gastrointestinal bleeding Advanced renal impairment or risk for renal failure History of other medical problems that could interfere with the study participation Pregnancy or breastfeeding Participation in another investigational study within past 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Intranasal Ketorolac Tromethamine<br> | Drug: Intranasal Ketorolac Tromethamine<br>* Intranasal at 30mg<br>|
| Placebo Comparator: Intranasal Placebo<br> | Drug: Intranasal Placebo<br>* Intranasal Placebo<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 |
| --- | --- | --- |
| Pain intensity difference 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. 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. | Prior to receiving study drug and at 20, 40, and 60 minutes, and 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42, and 48 hours after the first dose, then prior to each dose up to 72 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. | Prior to receiving study drug and at 20, 40, and 60 minutes, and 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42, and 48 hours after the first dose, then prior to each dose up to 72 hours | 
| 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 | 
| Morphine sulfate consumption at 24, 48, and 72 hours |  | 24, 48, and 72 hours after drug administration |