Intravenous Ketorolac Vs. Morphine In Children With Acute Abdominal Pain (KETOAPP)

Intravenous Ketorolac Vs. Morphine In Children Presenting With Acute Abdominal Pain And/or Suspected Appendicitis: A Multi-centre Non-Inferiority Randomized Controlled Trial

Appendicitis is a common condition in children 6-17 years of age, and the top reason for emergency surgery in Canada. Children with appendicitis can have very bad pain in their belly. Children often need pain medications given to them through a needle in their arm called an intravenous (IV). The most common IV pain medication is a type of opioid called morphine. We know that opioids work well to improve pain, but there are risks and side effects when taking them. There are non-opioid medications that doctors can give to patients, like ketorolac. Ketorolac helps decrease inflammation and pain and has fewer side effects when a patient takes it for a short period of time. Our past and present overuse of opioids, driven by an unproven assumption that opioids work best for pain, resulted in an Opioid Crisis and doctors are now looking for alternatives. To do this, we need to prove that there are other options to treat children's pain that are just as good as opioids, with less side effects.

The goal of our study is to discover if school aged children who arrive at the emergency department with belly pain, improve just as much with ketorolac as they do with morphine. To answer this question, we will need a very large number of patients in a study that includes several hospitals across Canada. With a flip of a coin, each participant will either get a single dose of morphine or a single dose of ketorolac. To make sure that our pain assessment is impartial, no one will know which medicine the child received except the pharmacist who prepared the medicine.

Study Overview

• Status: Recruiting
• Conditions: Emergencies; Abdominal Pain; Acute Pain; Appendicitis; Child, Only; Abdomen, Acute
• Intervention / Treatment: Drug: Ketorolac Tromethamine; Drug: normal saline; Drug: Morphine Sulfate; Drug: Normal saline

Detailed Description

Background: Appendicitis, the most common surgical diagnosis in Canadian children aged 6-17 years, accounts for ~8000 admissions annually. Despite an ongoing opioid crisis, prescription narcotics remain a mainstay analgesic for children with suspected appendicitis. Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), which has a safer adverse event (AE) profile than opioids, is commonly used in emergency departments (EDs) for adults; however, use in children is considered off label due to a lack of randomized trials in this patient population. We propose a multi-centre clinical trial to address this knowledge gap,informed by our team's successful pilot trial.

Specific Aim 1: To determine if administering intravenous (IV) ketorolac is non inferior to IV morphine in reducing mean pain scores in children with suspected appendicitis.

Hypothesis: IV ketorolac will be non-inferior to IV morphine

Specific Aim 2: To determine between group differences in rates of AEs. Hypothesis: IV ketorolac will be associated with less AEs than IV morphine.

Design: A randomized quadruple blind (participant, clinician, outcome assessor, investigator) parallel group double-dummy trial in 4 Canadian pediatric EDs. Eligible patients will be 6-17 years with 5-days of moderate-severe pain (vNRS ≥5 ) being investigated for suspected appendicitis, with intravenous (IV) access, will be randomized to either:

1. IV ketorolac 0.5 mg/kg up to 30 mg (intervention) + IV morphine placebo (normal saline), or
2. IV morphine 0.1 mg/kg up to 5 mg (active control) + IV ketorolac placebo (normal saline).

Primary outcome: Between-group mean difference in pain on the vNRS at 60 minutes following administration.

Safety outcome: Proportion of children experiencing AEs related to study drug administration.

Secondary Outcomes: Between-group differences: (1) pain relief as measured on vNRS at 30, 90 and 120 minutes and at 6-8 hours; (2) proportion who achieves a 2-point vNRS (minimal important difference) pain score reduction at 60 and 120 minutes; (3) proportion of patients who change their baseline pain category (vNRS: mild 0-3, moderate 4-6, severe ≥7) at each time point; (4) time to effective analgesia as measured by the time when vNRS of <3 is achieved (5) proportion of patients requiring additional analgesia; (6) total opioids administered (i.e., morphine equivalent mg/kg within 8 hours of treatment); (7) frequency of specific types of AEs (e.g., dizziness); (8) frequency of delayed appendicitis diagnosis; and (9) Ramsay Sedation Score at 30, 60, 90 and 120 minutes.

Sample size:With a non-inferiority margin of 1.0 (50% of the minimal important difference), 600 participants would give a power of 0.9 (1- β) to establish non-inferiority of ketorolac vs. morphine (significance level α = 0.05).

• Study Type: Interventional
• Enrollment (Estimated): 495
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Angela Wallace; Phone Number: 403-955-5451; Email: angela.wallace@ahs.ca
• Study Contact Backup: Name: Mohamed M Eltorki, MBChB, MSc; Phone Number: +1403-955-7723; Email: mmeltork@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital Emergency Department
      • Contact: Angela Wallace; Phone Number: 403-955-5451; Email: angela.wallace@ahs.ca
      • Contact: Mohamed Eltorki, MBChB, MSc; Phone Number: 403-905-7723; Email: mmeltork@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 6 to 17 years
2. Abdominal pain ≤5 days duration
3. Acute abdominal pain that is being investigated (suspected) by the clinical team for appendicitis
4. Patient with IV cannula in situ or ordered
5. Currently experiencing moderate to severe abdominal pain at rest or with movement: self-reported pain score ≥5 using the verbal Numerical Rating Scale

Exclusion Criteria:

1. Previous enrollment in the trial
2. NSAID use within 3 hours and/or opioid use within 1 to 2 hours (1 hour post-IV or intra-nasal fentanyl and 2 hours post IV morphine).
3. Children who need immediate resuscitation, are hemodynamically unstable as deemed by the clinical team or have a Canadian Triage Assessment Score of 1
4. Significant caregiver and/or child cognitive impairment precluding the ability to complete study questions.
5. Chronic pain requiring daily analgesic use: confounding as response to analgesics maybe altered.
6. History of severe undiagnosed gastrointestinal bleeding requiring medical intervention, peptic or duodenal ulcer disease or inflammatory bowel disease, coagulation disorders, prior cerebrovascular bleeding, known arterio-vascular malformations. History of minor gastrointestinal bleeding from conditions such as resolved fissures, polyps or allergic colitis will not exclude patients from participating.
7. History of chronic and active interstitial kidney disease
8. History of chronic and active hepatocellular disease: ketorolac is metabolized by the liver.
9. Known or suspected pregnancy at the time of enrollment or breastfeeding females
10. Known hypersensitivity to NSAIDs or opioids.
11. Absence of a parent/guardian for children who are <16 years of age if they are not a mature minor.
12. Inability to obtain consent due to a language barrier and the absence of language translator in person or by a phone translation service available in the ED.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketorolac Tromethamine; Ketorolac tromethamine, an NSAID belonging to a group of non-opioid analgesics that inhibit the synthesis of prostaglandins and thromboxanes with strong analgesic and anti-inflammatory properties. It is the only non-opioid parenteral non-sedating analgesic available in Canada for use to treat acute pain in the emergency department.	Drug: Ketorolac Tromethamine; Intravenous ketorolac given at 0.5 mg/kg of body weight up to a maximum of 30 mg in a single dose.; Drug: normal saline; Intravenous normal saline placebo (labelled as morphine) given at 0.1 mg/kg of body weight up to a maximum of 5 mg in a single dose.; Other Names: Morphine Sulfate Placebo
Active Comparator: Morphine Sulfate; An intravenous opioid that is commonly used as part of usual care for treament of pain in patients with acute abdominal pain and suspected appendicitis.	Drug: Morphine Sulfate; Intravenous morphine given at 0.1 mg/kg of body weight up to a maximum of 5 mg in a single dose.; Drug: Normal saline; Intravenous normal saline placebo (labelled as ketorolac) given at 0.5 mg/kg of body weight up to a maximum of 30 mg in a single dose.; Other Names: Ketorolac Tromethamine Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain relief as measured on the verbal numerical rating scale	Between group mean differences in pain as measured on an 11-point verbal Numerical Rating Scale (0 is no pain and 10 is worst pain ever)	60 minutes post drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain relief as measured on the verbal numerical rating scale	Between group mean differences in pain as measured on an 11-point verbal	30 minutes post drug administration
Pain relief as measured on the verbal numerical rating scale	Between group mean differences in pain as measured on an 11-point verbal	90 minutes post drug administration
Pain relief as measured on the verbal numerical rating scale	Between group mean differences in pain as measured on an 11-point verbal	120 minutes post drug administration
Pain relief as measured on the verbal numerical rating scale	Between group mean differences in pain as measured on an 11-point verbal	6 hours post drug administration
Pain relief as measured on the verbal numerical rating scale during the ultrasound diagnostic	score from 0-10 on verbal numerical rating scale	up to 6 hours post drug administration
Proportion who achieve the minimal important difference for pain relief	Proportion of participants who achieves the 2-point verbal Numerical Rating Scale minimal important difference pain score reduction	60 minutes post drug administration
Proportion who achieve the minimal important difference for pain relief	Proportion of participants who achieves the 2-point verbal Numerical Rating Scale minimal important difference pain score reduction	120 minutes post drug administration
Change in baseline pain category	Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7)	30 minutes post drug administration
Change in baseline pain category	Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7)	60 minutes post drug administration
Change in baseline pain category	Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7)	90 minutes post drug administration
Change in baseline pain category	Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7)	120 minutes post drug administration
Change in baseline pain category	Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7)	6 hours post drug administration
Time to effective analgesia	Duration of time from time of drug administration to time at which a verbal Numerical Rating Scale ≤3 is achieved.	up to 6 hours post drug administration
Additional analgesia requirment	Proportion of participants requiring any additional analgesia in each trial arm	up to 6 hours post drug administration
Total opioids administered	total morphine-equivalent mg/kg administered for all trial participants	up to 8 hours post drug administration
Ramsay sedation score	Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive)	30 minutes post drug administration
Ramsay sedation score	Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive)	60 minutes post drug administration
Ramsay sedation score	Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive)	90 minutes post drug administration
Ramsay sedation score	Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive)	120 minutes post drug administration
Adverse events per participant	Frequency of specific adverse event occurrence per participant enrolled	up to 6 hours post drug administration
Frequency of each specific adverse event	Frequency of each specific adverse event occurrence	up to 6 hours post drug administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Appendix visualization on ultrasound	proportion of participants who had the appendix visualized on ultrasound	post-randomization and up to 8 hours post-intervention.

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Mohamed Eltorki, MBChB, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2024
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: November 29, 2023
• First Posted (Actual): December 7, 2023

Study Record Updates

• Last Update Posted (Actual): June 24, 2024
• Last Update Submitted That Met QC Criteria: June 21, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Pain; Neurologic Manifestations; Disease Attributes; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Emergencies; Abdominal Pain; Acute Pain; Appendicitis; Abdomen, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; 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; Analgesics, Opioid; Narcotics; Ketorolac; Morphine; Ketorolac Tromethamine
• Other Study ID Numbers: 23-0952

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: At the completion of the study and publication of main manuscript, anonymized participant data can be shared upon reasonable request.
• IPD Sharing Time Frame: within 10 years of study completion
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No