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

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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• New Zealand
  • Hamilton, New Zealand
    • Waikato Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Intranasal post-surgery for up to 5 days total
EXPERIMENTAL: Ketorolac tromethamine	Drug: Ketorolac tromethamine; 30 mg intranasal post-surgery for up to 5 days total

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
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

Collaborators and Investigators

• Sponsor: Egalet Ltd

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (ACTUAL): June 1, 2005
• Study Completion (ACTUAL): June 1, 2007

Study Registration Dates

• First Submitted: May 3, 2011
• First Submitted That Met QC Criteria: May 3, 2011
• First Posted (ESTIMATE): May 4, 2011

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 2003-01