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

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: Intranasal Placebo; Drug: Intranasal Ketorolac Tromethamine

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 3

Contacts and Locations

Study Locations

• New Zealand
  • Hamilton, New Zealand
    • Waikato Clinical Research
• United States
  • California
    • Arcadia, California, United States, 91007
      • Methodist Hospital
    • Glendale, California, United States, 91206
      • Glendale Adventist Medical Center
    • Pasadena, California, United States, 91105
      • Clinical Management Services, Inc.
  • Texas
    • Houston, Texas, United States, 77054
      • Houston Perinatal Associates
    • Houston, Texas, United States, 77024
      • Memorial Hermann Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intranasal Ketorolac Tromethamine	Drug: Intranasal Ketorolac Tromethamine; Intranasal at 30mg
Placebo Comparator: Intranasal Placebo	Drug: Intranasal Placebo; Intranasal Placebo

What is the study measuring?

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
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
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
Morphine sulfate consumption at 24, 48, and 72 hours		24, 48, and 72 hours after drug administration

Collaborators and Investigators

• Sponsor: Egalet Ltd
• Investigators: Study Chair: Lincoln Bynum, MD, ICON Clinical Research

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): February 1, 2007

Study Registration Dates

• First Submitted: December 16, 2005
• First Submitted That Met QC Criteria: December 16, 2005
• First Posted (Estimate): December 19, 2005

Study Record Updates

• Last Update Posted (Estimate): February 8, 2017
• Last Update Submitted That Met QC Criteria: February 6, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketorolac; Ketorolac Tromethamine
• Other Study ID Numbers: ROX 2005-01