Comparison of Ketorolac at Three Doses in Children With Acute Pain

Migraine Clinical Trial

— KETODOSE  

Official title:

Comparison of Ketorolac at Three Doses in Children With Acute Pain: A Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05641363
• Other study ID #: KETODOSE20221107
• Status: Recruiting
• Phase: Phase 3
• Start date: June 1, 2023
• Est. completion date: February 2025

Study information

• Verified date: September 2023
• Source: Hamilton Health Sciences Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hospital Scene #1: A 6-year-old arrives in the Emergency Department at McMaster Children's Hospital (MCH) complaining of pain in his lower right side. His Dad explains the pain has been going on for a few hours and that Advil and Tyelnol haven't helped at all. He's anxious and concerned about his son because he never complains about pain - so this must be bad. After he has been seen by the doctor, the appendix appears to be the problem and the boy needs to have it removed. Dad wants his son's pain to go away but is worried because he once got a high dose of a medication and had some unwanted side effects.

Hospital Scene #2: A 14-year-old girl has been experiencing migraine headaches for the past months and is awaiting an appointment with a specialist. Today, however, the pain is the worst it's been. Mom has picked her up from school and brought her to MCH not knowing what else to do to help her. The Advil and Tylenol have not improved her pain. She desperately wants the pain to go away but is worried because she read that some pain medicines are used without any studies done to see if they work and if they are safe. (https://www.ottawalife.com/article/most-medications-prescribed-to-children-have-not-been-ade quately-studied?c=9).

In both cases, these children need medicine to help their pain. The treating doctors want to give them pain medicine that will 1) be safe and 2) make the pain go away. This is what parents and the child/teenager, and the doctors want too. Some pain medicines like opioids are often used to help with pain in children. Unfortunately, opioids can have bad side effects and can, when used incorrectly or for a long time, be addictive and even dangerous. A better option would be a non-opioid, like Ketorolac, which also helps pain but is safer and has fewer side effects. The information doctors have about how much Ketorolac to give a child, though, is what has been learned from research in adults. Like with any medication, the smallest amount that a child can take while still getting pain relief is best and safest. Why give more medicine and have a higher risk of getting a side effect, if a lower dose will do the trick? This is what the researchers don't know about Ketorolac and what this study aims to find out.

Children 6-17 years old who are reporting bad pain when they are in the Emergency Department or admitted in hospital and who will be getting an intravenous line in their arm will be included in the study. Those who want to participate will understand that the goal of the study is to find out if a smaller amount of medicine improves pain as much as a larger amount. By random chance, like flipping a coin, the child will be placed into a treatment group. The difference between these treatment groups is the amount of Ketorolac they will get. One treatment will be the normal dose that doctors use at MCH, and the other two doses will be smaller. Neither the patient, parent nor doctor will know how much Ketorolac they are getting. Over two hours, the research nurse or assistant will ask the child how much pain they are in. Our research team will also measure how much time it took for the pain to get better, and whether the child had to take any other medicine to help with pain. The research team will also ask families and patients some questions to understand their perceptions of pain control, pain medicines and side effects they know of.

This research is important because it may change the way that doctors treat children with pain, not just at MCH but around the world. The results of this study will be shared with doctors through conferences and scientific papers. It's also important that clinicians share information with parents and children so that they can understand more about pain medicines and how these medicines can be used safely with the lowest chance of side effects.

Description:

Comparison of Ketorolac at Three Doses In Children With Acute Pain: A Randomized Controlled Trial (KETODOSE TRIAL)

Background: Despite the ongoing opioid crisis, opioids remain a commonly prescribed analgesic for patients with acute pain. Ketorolac is the leading parenteral non-steroidal anti-inflammatory drug (NSAID) in Canada commonly used in the Emergency Department (ED) and inpatient settings for acute abdominal pain and migraine headaches. Though it has safer adverse event profile than opioids, its use in children is off label as there are virtually no pediatric trials to inform this practice. Currently the recommended dosing for children is 0.5 mg/kg to a maximum dose of 30 mg. Recent trials with adults have shown no added analgesic benefit to higher doses of ketorolac, when comparing 10 mg to 15 mg or 30 mg, intravenous (IV). A lower dose will be desirable if it achieves similar reduction of pain, as it allows for safer cumulative daily dosing and lower rates of adverse events. This has led many physicians to change their adult practice to a maximum dose of 10 mg IV; however, despite their smaller size, most children continue to be exposed to doses of 30 mg IV, due to a lack of similar available evidence.

Research Question: In children aged 6 - 17 years, with moderate to severe pain (measured using the 11-point verbal numerical rating scale (VNRS)), who are prescribed IV Ketorolac by their treating physician, is low-dose IV Ketorolac (0.25 mg/kg/dose up to 10 mg OR 0.5 mg/kg/dose up to 10 mg) non-inferior (NI) to standard treatment (0.5 mg/kg/dose up to 30 mg) in reducing mean pain scores within a NI margin of 1?

Study Design: Our trial is a single-center, block randomized, double-dummy, double-blind, three-arm, controlled trial with parallel groups. Participants will include: (i) ≥6 years; (ii) with moderate-severe pain (defined as VNRS > 4; (iii) seen in the ED or inpatient setting; and (iv) who have an IV access planned/available. These individuals will be randomized to an arm with active ketorolac and a 'placebo' ketorolac of a differing dose, to maintain blinding through the double-dummy design: (1) standard-dose ketorolac (0.5 mg/kg IV up to 30 mg IV) + low-dose ketorolac placebo; (2) low-dose ketorolac (0.25 mg/kg up IV up to 10 mg IV) + standard-dose ketorolac placebo; or (3) low-dose ketorolac (0.5 mg/kg IV up to 10 mg) + standard-dose ketorolac placebo.

Participants will be allowed any other non-NSAID rescue therapy at any point after our trial drugs are administered, based on clinical team discretion. Based on available adult literature, a chosen NI margin of 1 point (50% of the established MID), an expected mean difference of 0.2 on the VNRS, and standard deviation of 1.5 points, 57 participants will be needed in each group to achieve a 5% alpha at 80% power.

Primary Outcomes: Between each low-dose ketorolac group and standard group mean differences in pain as measured on VNRS at 60 minutes.

Summary: Acute pain requiring parenteral analgesia is very common amongst Canadian children.Despite data in adults and children supporting preferential NSAID use for acute pain, significant gaps in knowledge regarding safe and effective Ketorolac dosing in children still exists. The drug's superior adverse effect profile and lack of dependence and abuse potential, makes this an appropriate than opioids, and is not known to be a substance of misuse.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 171
• Est. completion date: February 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

Inclusion Criteria:

1. Age 6.0 years to <18 years: primary outcome measure, 11-point vNRS is validated for use in children =6 years, and no other evidence-based acute pain measure is recommended for use in younger children Currently experiencing moderate to severe pain (self-reported pain score >4 using the vNRS at the time of enrollment; ketorolac is used to treat moderate to severe pain)

2. Patients seen in the ED or inpatient setting with acute pain =30 days in duration

3. Patient with IV cannula in situ or ordered (to minimize any additional pain or distress)

Exclusion Criteria:

1. Previous enrollment in trial (to ensure all observations are independent and not paired)

2. Post-operative patient (as this included medically induced pain, versus pathology-only)

3. Ketorolac 6 hours and/or opioids 4 hours prior to recruitment (avoid over-dosing and confounding)

4. Use of daily analgesic for any indications (confounding as response to analgesics maybe altered)

5. Caregiver and/or child cognitive impairment (precludes the ability to respond to study questions)

6. History of gastrointestinal bleed or ulcers, inflammatory bowel disease, coagulation disorders, cerebrovascular bleeding, known arterio-vascular malformations (increased bleeding risk)

7. History of chronic and active renal disease, excluding renal calculi and urinary tract infections

8. History of chronic and active hepatocellular disease (ketorolac is metabolized in the liver)

9. Known pregnancy at the time of enrollment (risk of closure of patent ductus arteriosus in fetus)

10. Known hypersensitivity to NSAIDs or opioids

11. Inability to obtain consent (language barrier and the absence of language translator)

Related Conditions & MeSH terms

• Abdominal Pain
• Acute Pain
• Appendicitis
• Appendicitis Acute
• Biliary Colic
• Colic
• Migraine
• Renal Colic

Intervention

Drug:
• 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 for use to treat acute pain in the emergency department.

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	McMaster University Medical Centre	Hamilton	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Hamilton Health Sciences Corporation	McMaster University

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety outcome 1	The proportion of children experiencing any adverse events (AEs), as reported by caregivers or clinical staff, will be recorded in accordance with the CONSORT Harms checklist. We will solicit specific expected AEs that are commonly reported with NSAIDs such as gastric pain. Additionally, we will have open-ended questions to collect information on any additional unexpected AEs.	Within 8 hours post study drug administration
Other	Safety outcome 2	Frequency of each specific AE (e.g., nausea, vomiting)	Within 8 hours post study drug administration
Other	Survey to understand patients' and caregivers' knowledge, attitudes, perceptions, and emotions on pain, medications, and their use in treating acute pain.	Semi-structured survey with baseline demographics, closed-ended questions (7-point Likert scale)	Within 7-days of pain outcome completion.
Primary	Pain relief	Between each low-dose ketorolac group (B1 and B2) and standard group (A) 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	Pain relief	11-point verbal Numerical Rating Scale (0 is no pain and 10 is worst pain ever) score at 30, 90 and 120 minutes as well as 6 to 8 hours post administration.	8 hours post study drug administration
Secondary	Pain relief by a minimally important difference (MID)	Proportion of participants who achieves the 2-point reduction in the 11-point verbal numerical rating scale MID pain score reduction.	60 and 120 minutes post study drug administration
Secondary	Change in category of pain	Proportion of participants who change the severity of their baseline pain category at all time points (mild = 0 to 3, moderate = 4 to 6, severe =7 on the verbal numerical rating scale)	30, 90, 120 minutes and 6 hours post study drug administration
Secondary	Time to effective analgesia	time at which a verbal numerical rating scale <3 is achieved post-intervention	Within 8 hours post study drug administration
Secondary	Rescue analgesia use	Proportion of participants requiring rescue analgesia in each trial arm	Within 8 hours post study drug administration
Secondary	Opioid sparing	The total amount of opioids administered as measured by morphine equivalent mg/kg	Within 8 hours post study drug administration