Ketorolac for Moderate to Severe Abdominal Pain in Children (KETO-APP)

Intravenous Ketorolac Vs. Morphine In Children Presenting With Suspected Appendicitis: A Pilot Single Center Non Inferiority Randomised Controlled Trial

In children and adolescents (older than 6 years in age) who arrive in the pediatric emergency department because they have been having 5 days or less of abdominal pain (possible appendicitis), will patients who are treated with ketorolac get just as much pain relief as those patients treated with morphine?

To answer this research question, we will need a large number of patients in a study. To ensure we have enough patients, we must include many hospitals in different cities and provinces in the same study. Before doing this, though, we must first test a smaller version of the study in our center at McMaster Children's hosptial. The goal of doing this at McMaster first is to make sure or understand:

1. We can enroll enough people in our study over 1 year
2. We can make sure that all the information we collect from patients is complete and nothing is missing
3. Reasons behind why people don't want to participate in the study
4. How satisfied patients and their caregivers were with the study

Study Overview

• Status: Completed
• Conditions: Emergencies; Analgesia; Abdominal Pain; Appendicitis; Child, Only
• Intervention / Treatment: Drug: Ketorolac Tromethamine 10 MG/ML; Drug: Morphine Sulfate 10Mg/1mL Injection

Detailed Description

Background/Rationale: Appendicitis is the most common emergent surgical diagnosis among children between 5-17 years in age and accounts for 8000 admissions annually. Diagnosing appendicitis is time consuming (4-6 hours) as it requires laboratory tests and ultrasonography. This occurs while patients experience significant abdominal pain secondary to infection and localized or generalized peritonitis. Opioids have been the most prescribed analgesic for patients with suspected appendicitis, despite an ongoing opioid crisis. Our research shows that 60% of physicians use morphine or other opioids, while 40% will use non-steroidal anti-inflammatory drug (NSAID) or other non-opioids. Even though ketorolac (NSAID) is commonly used in the Emergency Department (ED) for renal colic, abdominal pain and migraine headaches, and has a safer side effect profile than morphine, all such uses in children are "off label" as there are virtually no controlled trials for children to inform practice.

Objective: To determine if it is feasible to conduct a large multi-centre randomized non inferiority trial comparing ketorolac to morphine for treating moderate to severe abdominal pain, in children 6 years in age or older, with clinically suspected appendicitis.

Hypothesis: We hypothesize that it will be feasible to conduct a large trial based on a recruitment rate of ≥40% of eligible patients approached for consent.

Study Design: Our trial is a single-centre, block randomized, non-inferiority, double-dummy, doubleblind, feasibility pilot trial. Patients ≥ 6 years in age, who have ≤ 5 days of moderate-severe pain as defined by our validated 11-point verbal numeric rating scale (VNRS) ≥ 5 and are being investigated for suspected appendicitis with intravenous (IV) access in situ or ordered, will be randomized to either: (1) IV ketorolac 0.5 mg/kg up to 30 mg (intervention) + IV morphine placebo, or (2) IV morphine 0.1 mg/kg up to 5 mg (active control) + IV ketorolac placebo. The total sample size is 100 participants. The study drugs will be identical in appearance, consistency and smell. The double-dummy design will ensure blinding is maintained for bedside clinical staff, research personnel and patients. Our study prioritized patient comfort and will largely mimic standard care. Pharmacologic co-interventions will be allowed but limited to acetaminophen (commonly used as first-line therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg) within 60 minutes of our intervention. We will screen the ED daily for eligible patients as well as include all eligible patients for the New Investigator Fund (NIF)-funded quality improvement pathway we employed to streamline care for all ED appendicitis patients. We have a robust research program in the ED that includes students, a full-time research coordinator and several paid research assistants who screen eligible patients and approach them for consent and enrollment. Our entire project can be completed with NIF support within an 18-month study period.

Primary Outcome: Feasibility of our study design is the primary outcome of this pilot trial. Primary feasibility outcomes include: (1) proportion of patients consented from total eligible patients approached; (2) proportion of patients who completed clinical outcome assessment; and, (3) proportion of missing items on individual data collection forms. Our feasibility threshold is to recruit at least 40% of eligible patients who were approached to consent. Other thresholds include recruiting ≥8 participants/month on average and having at least 90% of participants complete all the outcome assessments at 30, 60, 90 and 120 minutes.

Summary: Acute pain in children and youth is an area that is understudied and affects thousands of Canadian children. Despite short -and long-term adverse effects including dependence, and well designed comparative effectiveness trials, opioids continue to be overused in surgical patients. Ketorolac is a promising well-established NSAID that is available for IV, has a better short-term side effect profile and is not known as a substance of misuse. Our pilot will provide valuable feasibility data for a larger, future multicenter trial.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mohamed M Eltorki, MBChB; Phone Number: 76472 905-521-2100; Email: eltorkim@mcmaster.ca
• Study Contact Backup: Name: Lehana Thabane, PhD; Phone Number: 34905 905-525-9140; Email: thabanl@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L9H6k6
      • McMaster Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 6.0 years to <18 years: Children aged < 6 years of age at low risk for appendicitis and often present atypically.46,47
2. Duration of abdominal pain ≤ 5 days: Children with longer durations of acute abdominal pain are less likely to have appendicitis.18,48
3. A clinical decision to investigate for appendicitis as a possible etiology by the ED MD or RN. The physician or bedside nurse are suspicious of a diagnosis of appendicitis as a cause for the abdominal pain as reflected by the initiation of the appendicitis medical directive (an advanced nursing directive that allows nurses to order tests for patients with suspected appendicitis) and order laboratory tests and/or advanced imaging or directly consult pediatric surgery to rule out appendicitis.
4. Patient has an IV cannula in situ or ordered to be placed: we will not include patients without an IV ordered or established in order to ensure the study intervention is limited to the study drugs and is not associated with the performance of any invasive procedures.
5. Currently experiencing moderate to severe pain: self-reported pain score ≥5 using the VNRS at the time of enrollment.

Exclusion Criteria:

1. Previous enrollment in trial (to ensure all observations are independent and not paired)
2. NSAID use within 3 hours and/or opioid use within 2 hours prior to recruitment to avoid over-dosing and confounding
3. Caregiver and/or child cognitive impairment precluding the ability to self-report pain or respond to study questions
4. Chronic pain requiring daily analgesic use for other indications (e.g. naproxen for juvenile idiopathic arthritis): confounding
5. History of gastrointestinal bleeding, peptic or duodenal ulcer disease or inflammatory bowel disease, coagulation disorders, prior cerebrovascular bleeding, known arterio-vascular malformations: Bleeding risk
6. History of chronic and active renal disease, excluding renal calculi and urinary tract infections
7. History of chronic and active hepatocellular disease (excludes biliary stones, cholangitis or biliary duct pathology), as ketorolac is metabolized in the liver.
8. Known pregnancy at the time of enrollment, a positive pregnancy test in females ≥ 12 years in age or breastfeeding females due to the risk of premature closure of patent ductus arteriosus
9. Known hypersensitivity to NSAIDs or opioids (e.g. naproxen, ibuprofen, acetylsalicylic acid, ketoprofen or ketorolac, morphine, hydromorphone, fentanyl)
10. Absence of a parent/guardian for children who are < 16 years in age: youths who are ≥16 years can provide us with informed consent without the permission of a guardian
11. Inability to obtain consent due to a significant language barrier, in the absence of a native language translator

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; IV ketorolac tromethamine, 0.5 mg/kg to a maximum of 30 mg plus IV morphine placebo;	Drug: Ketorolac Tromethamine 10 MG/ML; Non-Steroidal-Anti-Inflammatory given intravenously.
Active Comparator: Morphine Sulfate; IV morphine 0.1 mg/kg to a maximum of 5 mg plus IV ketorolac placebo	Drug: Morphine Sulfate 10Mg/1mL Injection; Opioid commonly used for acute abdominal pain given intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility Outcomes	proportion of patients consented from total eligible patients approached	2 hours
Feasibility Outcomes	Proportion of participants who completed outcome assessment at all time points	2 hours
Feasibility Outcomes	Proportion of missing items on individual data collection forms (screening forms, baseline characteristics, outcome assessment, follow up survey)	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Satisfaction	Proportion of participants and caregivers who were satisfied with study procedures and interventions, on an 0-11 numeric satisfaction survey	14 days
Declining consent	percentage and reasons for declining consent	2 hours
withdrawing consent	proportion of patients who withdrew consent	2 hours
full study completion	proportion of patients who fully completed the study (baseline characteristics, outcome assessment and follow-up survey).	14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Outcomes	Within-group mean and standard deviation differences in pain as measured on verbal numerical pain scale (VNRS) for ketorolac and morphine at 30, 60, 90 and 120 minutes	2 hours
Clinical Outcomes	Proportion of participants who change their baseline pain category (mild 1 to 3, moderate 4 to 6, severe ≥7 on VNRS)	2 hours
Clinical Outcomes	Proportion of participants who achieved their desired pain state as determine on a numeric satisfaction scale (0-10)	2 hours
Clinical Outcomes	Time to effective analgesia (VNRS <3)	2 hours
Clinical Outcomes	Proportion of participants requiring rescue analgesia in each trial arm and the total amount administered as measured by morphine equivalent mg/kg within 6 hours of intervention	6 hours
Clinical Outcomes	Frequency of missed appendicitis (diagnosed on a return visit within 7 days)	14 days
Clinical Outcomes	Proportion of patients who had complete visualization of the appendix on ultrasound	24 hours

Collaborators and Investigators

• Sponsor: Hamilton Health Sciences Corporation
• Investigators: Principal Investigator: Mohamed Eltorki, MBChB, McMaster University

Publications and helpful links

General Publications

• Eltorki M, Busse JW, Freedman SB, Thompson G, Beattie K, Serbanescu C, Carciumaru R, Thabane L, Ali S. Intravenous ketorolac versus morphine in children presenting with suspected appendicitis: a pilot single-centre non-inferiority randomised controlled trial. BMJ Open. 2022 Apr 5;12(4):e056499. doi: 10.1136/bmjopen-2021-056499.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2021
• Primary Completion (Actual): February 5, 2023
• Study Completion (Actual): February 6, 2023

Study Registration Dates

• First Submitted: August 23, 2020
• First Submitted That Met QC Criteria: August 23, 2020
• First Posted (Actual): August 27, 2020

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 27, 2023
• Last Verified: February 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; Appendicitis; 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: 582125

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Data and study-related documents will be available when the database has been locked and data has been unblinded.
• IPD Sharing Access Criteria: The data that support the findings of this study are available from the corresponding author (M.E), upon reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No