Abdominal PainPhase 3KETO-APPNCT04528563
Ketorolac for Moderate to Severe Abdominal Pain in Children
A Phase 3 study testing Ketorolac Tromethamine 10 MG/ML and Morphine Sulfate 10Mg/1mL Injection in people with Abdominal Pain and Appendicitis, run by Hamilton Health Sciences Corporation at 1 site in Canada.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 6 to 17 years
- Conditions the study is for
- Abdominal Pain, Appendicitis, Analgesia
- What is being tested?
- Ketorolac Tromethamine 10 MG/ML and Morphine Sulfate 10Mg/1mL Injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 105 participants
- Where
- 1 siteCanada
- Study dates
- 5 May 2021to 6 Feb 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Age 6.0 years to <18 years: Children aged < 6 years of age at low risk for appendicitis and often present atypically.46,47
- Duration of abdominal pain ≤ 5 days: Children with longer durations of acute abdominal pain are less likely to have appendicitis.18,48
- 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.
- 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.
- Currently experiencing moderate to severe pain: self-reported pain score ≥5 using the VNRS at the time of enrollment.
Who cannot join
- Previous enrollment in trial (to ensure all observations are independent and not paired)
- NSAID use within 3 hours and/or opioid use within 2 hours prior to recruitment to avoid over-dosing and confounding
- Caregiver and/or child cognitive impairment precluding the ability to self-report pain or respond to study questions
- Chronic pain requiring daily analgesic use for other indications (e.g. naproxen for juvenile idiopathic arthritis): confounding
- History of gastrointestinal bleeding, peptic or duodenal ulcer disease or inflammatory bowel disease, coagulation disorders, prior cerebrovascular bleeding, known arterio-vascular malformations: Bleeding risk
- History of chronic and active renal disease, excluding renal calculi and urinary tract infections
Show all 11Show fewer
- History of chronic and active hepatocellular disease (excludes biliary stones, cholangitis or biliary duct pathology), as ketorolac is metabolized in the liver.
- 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
- Known hypersensitivity to NSAIDs or opioids (e.g. naproxen, ibuprofen, acetylsalicylic acid, ketoprofen or ketorolac, morphine, hydromorphone, fentanyl)
- 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
- Inability to obtain consent due to a significant language barrier, in the absence of a native language translator
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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:
- We can enroll enough people in our study over 1 year
- We can make sure that all the information we collect from patients is complete and nothing is missing
- Reasons behind why people don't want to participate in the study
- How satisfied patients and their caregivers were with the study
Read the 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.
- Conditions
- Abdominal Pain, Appendicitis, Analgesia, Child, Only, Emergencies
- Being tested
- Ketorolac Tromethamine 10 MG/ML, Morphine Sulfate 10Mg/1mL Injection
- Medical subject headings
- Abdominal Pain, Appendicitis, Agnosia, Emergencies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketorolac Tromethamine 10 MG/MLDrug
Non-Steroidal-Anti-Inflammatory given intravenously.
Morphine Sulfate 10Mg/1mL InjectionDrug
Opioid commonly used for acute abdominal pain given intravenously.
| Study group | Role | What they receive |
|---|---|---|
| Ketorolac Tromethamine | Experimental | IV ketorolac tromethamine, 0.5 mg/kg to a maximum of 30 mg plus IV morphine placebo; Receives: Drug: Ketorolac Tromethamine 10 MG/ML |
| Morphine Sulfate | Active comparator | IV morphine 0.1 mg/kg to a maximum of 5 mg plus IV ketorolac placebo Receives: Drug: Morphine Sulfate 10Mg/1mL Injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility Outcomes
proportion of patients consented from total eligible patients approached
Measured: 2 hours
Feasibility Outcomes
Proportion of participants who completed outcome assessment at all time points
Measured: 2 hours
Feasibility Outcomes
Proportion of missing items on individual data collection forms (screening forms, baseline characteristics, outcome assessment, follow up survey)
Measured: 14 days
Secondary outcomes (4)
Study Satisfaction
Proportion of participants and caregivers who were satisfied with study procedures and interventions, on an 0-11 numeric satisfaction survey
Measured: 14 days
Declining consent
percentage and reasons for declining consent
Measured: 2 hours
withdrawing consent
proportion of patients who withdrew consent
Measured: 2 hours
full study completion
proportion of patients who fully completed the study (baseline characteristics, outcome assessment and follow-up survey).
Measured: 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Aug 2020
- Study start5 May 2021
- Primary completion5 Feb 2023
- Study completion6 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Abdominal PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- double dummy design
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 105 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hamilton Health Sciences Corporation
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mohamed Eltorki, MBChB, Hamilton Health Sciences Corporation
- Investigators
- Mohamed Eltorki, MBChB, Principal investigator, McMaster University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04528563
- Sponsor's protocol ID
- 582125
- Acronym
- KETO-APP
- Status last verified
- Feb 2023
- First submitted
- 23 Aug 2020
- Last updated
- 28 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
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.
PubMed 35383071
Study at a glance
From the registry record, last updated by the sponsor on 28 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intravenous Ketorolac Vs. Morphine In Children Presenting With Suspected Appendicitis: A Pilot Single Center Non Inferiority Randomised Controlled Trial
- ClinicalTrials.gov ID
- NCT04528563
- Acronym / sponsor ID
- KETO-APP / 582125
- Conditions
- Abdominal Pain, Appendicitis, Analgesia, Child, Only, Emergencies
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 105 participants (actual)
- Lead sponsor
- Hamilton Health Sciences CorporationUniversity, hospital or other
- Study start
- 5 May 2021 (actual)
- Primary completion
- 5 Feb 2023 (actual)
- Study completion
- 6 Feb 2023 (actual)
- First posted
- 27 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- We can enroll enough people in our study over 1 year
- We can make sure that all the information we collect from patients is complete and nothing is missing
- Reasons behind why people don't want to participate in the study
- How satisfied patients and their caregivers were with the study
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- double dummy design
| Arm | Type | Receives |
|---|---|---|
| Ketorolac Tromethamine | Experimental | Drug: Ketorolac Tromethamine 10 MG/MLIV ketorolac tromethamine, 0.5 mg/kg to a maximum of 30 mg plus IV morphine placebo; |
| Morphine Sulfate | Active comparator | Drug: Morphine Sulfate 10Mg/1mL InjectionIV morphine 0.1 mg/kg to a maximum of 5 mg plus IV ketorolac placebo |
Who may qualify
- Ages
- 6 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Age 6.0 years to <18 years: Children aged < 6 years of age at low risk for appendicitis and often present atypically.46,47
- Duration of abdominal pain ≤ 5 days: Children with longer durations of acute abdominal pain are less likely to have appendicitis.18,48
- 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.
- 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.
- Currently experiencing moderate to severe pain: self-reported pain score ≥5 using the VNRS at the time of enrollment.
Key exclusion criteria (11 listed)
- Previous enrollment in trial (to ensure all observations are independent and not paired)
- NSAID use within 3 hours and/or opioid use within 2 hours prior to recruitment to avoid over-dosing and confounding
- Caregiver and/or child cognitive impairment precluding the ability to self-report pain or respond to study questions
- Chronic pain requiring daily analgesic use for other indications (e.g. naproxen for juvenile idiopathic arthritis): confounding
- History of gastrointestinal bleeding, peptic or duodenal ulcer disease or inflammatory bowel disease, coagulation disorders, prior cerebrovascular bleeding, known arterio-vascular malformations: Bleeding risk
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketorolac Tromethamine 10 MG/MLNon-Steroidal-Anti-Inflammatory given intravenously. | Drug | Ketorolac Tromethamine |
| Morphine Sulfate 10Mg/1mL InjectionOpioid commonly used for acute abdominal pain given intravenously. | Drug | Morphine Sulfate |
Primary outcome
Feasibility Outcomes
Time frame: 2 hours
proportion of patients consented from total eligible patients approached
Feasibility Outcomes
Time frame: 2 hours
Proportion of participants who completed outcome assessment at all time points
Feasibility Outcomes
Time frame: 14 days
Proportion of missing items on individual data collection forms (screening forms, baseline characteristics, outcome assessment, follow up survey)
4 secondary outcomes
Study Satisfaction
Time frame: 14 days
Declining consent
Time frame: 2 hours
withdrawing consent
Time frame: 2 hours
full study completion
Time frame: 14 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Feb 2023.
- Derived from this study: PubMed 35383071Eltorki 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.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mohamed Eltorki, MBChB principal investigator
McMaster University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ketorolac Tromethamine 10 MG/ML and Morphine Sulfate 10Mg/1mL Injection in people with Abdominal Pain and Appendicitis, run by Hamilton Health Sciences Corporation at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility Outcomes (time frame: 2 hours). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04528563, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2023.