CAST: A RCT of a Combination of Analgesics for Pain Management in Children With a Suspected Fracture

Sponsor

St. Justine's Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02985177

Collaborator

(none)

300

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

MSK-I is the most common cause for ED visits for children with pain, with a child's risk of sustaining a fracture ranging from 27-42% by the age of 16 years. MSK-I is known to generate moderate to severe pain in most children and the ED serves as the critical entry point for these injured children. This study aims to provide rapid and sustained pain management for children presenting with a MSK-I in the ED. The investigators will compare the efficacy of 2 possible medication combinations (fentanyl intranasal + oral hydromorphone or fentanyl intranasal + oral ibuprofen) for the rapid, adequate and sustained pain management of children with suspected fracture.

The investigators believe that the addition of HM to INF will lead to better pain treatment by providing a consistent and adequate level of analgesia throughout the entire ED visit, including prior to physician exam and during painful radiologic procedures.

Condition or Disease	Intervention/Treatment	Phase
Emergency Service, Hospital Child/Adolescent Problem Acute Pain Fentanyl Ibuprofen Analgesics, Opioid Anti-inflammatory Agents, Non-steroidal	Drug: Fentanyl intranasal + Oral Hydromorphone Drug: Fentanyl intranasal + Oral ibuprofen	Phase 4

Detailed Description

Pain management for children with a suspected fracture is suboptimal in the Emergency Department (ED). This type of musculoskeletal injury (MSK-I) often generates moderate to severe pain (> 49 mm on 0 to 100 mm Visual Analogue Scale (VAS)), and requires rapid and sustained pain management for the duration of the physical examination, diagnostic imaging (X-Ray), immobilization and occasionally fracture reduction. Current standard care includes the use of oral ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), for mild-to-moderate MSK-I pain in the ED. However, ibuprofen has been shown to be inadequate for moderate-to-severe pain when used alone. A number of small/single centre studies suggest that intranasal fentanyl (INF) is effective for rapidly decreasing MSK-I related pain in children. with a quick onset of 10 minutes and a peak action of 20 minutes. However, the duration of its analgesic effect is limited to a maximum of 60 minutes, which does not provide an optimal pain management for the duration of the ED stay, which typically lasts up to three hours. Oral hydromorphone (HM) is a long-acting opioid that is more potent but causes less side effects than oral morphine. Its analgesic effect lasts up to 4 hours, and its peak of action is at 60 minutes after administration. Similarly, ibuprofen's peak of action is also at 60 minutes and its analgesic effect lasts up to 6 hours. Typically, patients with a fracture have sustained pain throughout their ED stay due to imaging, splinting and repeated physical exams. Our objective is to examine the efficacy of a combination of intranasal and oral analgesics for pain management in children presenting to the ED with a suspected fracture. Our primary research question: For children presenting to the ED with a suspected fracture, is a combination of INF (1.5 mcg/kg, maximum dose of 100 mcg) and oral HM (0.04 mg/kg, maximum dose of 2 mg) more efficacious than a combination of INF (1.5 mcg/kg, maximum dose of 100 mcg) and oral ibuprofen (10 mg/kg, maximum dose of 600 mg) to decrease pain to < 30 mm (on a 0 to 100mm Visual Analog Scale) at 60 minutes post-administration? Our primary hypothesis is: A combination of INF and oral HM will be more efficacious than a combination of INF and oral ibuprofen to decrease pain to <30 mm at 60 minutes post-administration.

Methods. Design: This study is a double-blind, two-arm, four-centre RCT of a combination of analgesics for pain management of children presenting to the ED with a suspected fracture will be performed. Settings: Children will be recruited in the following EDs: CHU Sainte-Justine (Montreal, QC), Children Hospital of Eastern Ontario (Ottawa, ON), Stollery Children's Hospital (Edmonton, AB), and Children's Hospital of the London Health Sciences Centre (London, ON). Sample. Inclusion criteria: Will be include children: (a) with a pain score >49 mm on VAS at triage, (b) between the ages of 8 and 17 years, (c) presenting to the ED with a suspected fracture of the upper or lower limb, and (d) who can communicate in either French or English. Exclusion criteria: Will be exclude children with (a) known allergy to fentanyl, hydromorphone, ibuprofen, or artificial colouring, (b) triage nurse suspicion of child abuse, (c) inability to self-report pain, (d) chronic pain that necessitates daily analgesic use, (e) NSAID or opioid analgesic use within the three hours prior to ED presentation, (f) trauma to >1 limb, (g) known hepatic or renal disease/dysfunction, (h) known bleeding disorder, (i) neuro-cognitive disability that precludes assent and/or participating in the study, (j) known history of obstructive sleep apnea (k) a suspected fracture of the nose, or (l) significant head injury, as determined by the clinical team/triage nurse.

Allocation and Randomization: A biostatistician, independent to our study team, will generate the randomization scheme that will consist of a computer-generated random listing of the treatment using a 1:1 allocation scheme. Randomization will be stratified by center using block-randomization (with permuted block sizes). Enrolled children will be allocated to (a) INF 1.5 mcg/kg (up to a maximum of 100 mcg) via intranasal atomization + oral HM 0.04 mg/kg (up to a maximum of 2 mg) OR (b) INF 1.5 mcg/kg (up to a maximum of 100 mcg) via intranasal atomization + oral ibuprofen 10 mg/kg (up to a maximum of 600 mg. Sample Size: Sample size calculations were made to achieve a power of 90 % at an alpha level of 5 % in the comparison of the proportion of children with a pain intensity score of less than 30 mm on the VAS at T-60 between the group with intranasal fentanyl + oral hydromorphone and intranasal fentanyl

oral ibuprofen group. The investigators expect that this proportion will be 75 % in the group with intranasal fentanyl + oral hydromorphone and 50 % in the group with intranasal fentanyl + oral ibuprofen, these estimations are based on results of previous trials as well as results of studies using INF with children. Ba sed on our team's previous studies, 8 % of loss to follow-up is expect (LFUP) at T-60, and, as such, 300 children will be randomize into two groups (150/group). For the primary safety outcome the investigators anticipate that the serious adverse events (SAEs) will be rare. In the case where no SAEs are observed, a sample size of 138 (150 - 8% LFUP) will yield an upper limit for the 95% CI of 2.1% for the rate of SAEs per arm. Assuming a low 5% rate is observed in the INF + ibuprofen arm, an absolute difference in the rates of SAEs as low as 11% between the INF + ibuprofen arm and INF + HM arm (5% vs 16%) can be detected with 80% power and an alpha level of 5%. Primary efficacy outcome: Proportion of children in each analgesic group with a pain intensity score <30 mm at 60-minutes post-medication administration. The choice of measuring the proportion of children with pain <30 mm, as opposed to a more traditional measure of relative changes in VAS scores, reflects our team's commitment to patient-level outcomes; patients need to achieve a manageable (i.e. mild) level of pain to have reasonable functioning and satisfaction, as opposed to simply a relative decrease in pain. Primary safety outcome: Composite safety outcome where a safety event will be defined as: (a) clinical sedation (as measured by a score > 3 on the Ramsay Sedation Scale-RSS) [45], OR (b) a respiratory rate under the standardized normal minimal value for age, OR (c) an oxygen saturation level (SO2) <92% while breathing ambient (room) air, observed during the 120-min post-medication administration period. The RSS is a widely used, valid and reliable scale; it is the standard against which other sedation scales are compared. Secondary outcomes: (a) mean pain scores and mean differences in pain scores (between groups) at 10 min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during the medical examination (T-ME), and during radiographic procedure (T-XR), (b) the proportion of children administered a rescue analgesic in the 60 minutes following administration of study medication, (c) the proportion of children with side effects at T-10, T-20, T-30, T-60, T-90, T-120, T-ME and T-XR, (d) the proportion of children in each group with an RSS score between 1 to 3, (e) parental and child reports of acceptability of the medication at the end of the trial, and (f) self-reported levels of satisfaction of children and parents with pain management at the end of the study period.

Relevance: In response to the persistent problem of inadequate and delayed analgesia, the investigators believe that a combination of rapidly acting (INF) and longer-acting (oral HM or ibuprofen) medications will address both the delay in the time to effective analgesia and overall under-treatment of suspected fracture pain. The team anticipate that an RCT demonstrating the efficacy of a combination of fast and long-acting analgesics will significantly improve the treatment for children with a suspected fracture in the ED. The investigators hypothesize that use of INF and oral HM will provide rapid pain relief that is sustained for the duration of the ED visit. Promotion of adequate acute pain treatment of children presenting to the ED will prevent the known short and long-term effects of inadequately treated pain in children previously demonstrated by our team, including unpleasant memories, stress and anxiety upon future visits to healthcare and compromised functional outcomes such as missed school.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized Controlled Trial of a Combination of Analgesics for Pain Management in Children With a Suspected Fracture at Triage (CAST Trial)

Anticipated Study Start Date :

Dec 1, 2019

Anticipated Primary Completion Date :

Oct 1, 2020

Anticipated Study Completion Date :

Jun 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: INF + HM The participant will receive a dose of intranasal fentanyl (1.5 mcg/kg up to a maximum of 100 mcg) AND a dose of oral hydromorphone (0.04mg/kg up to a maximum of 2 mg).	Drug: Fentanyl intranasal + Oral Hydromorphone Analgesics
Active Comparator: INF + IBU The participant will receive a dose of intranasal (1.5 mcg/kg up to a maximum of 100 mcg) AND a dose of oral ibuprofen (10 mg/kg up to a maximum of 600 mg)	Drug: Fentanyl intranasal + Oral ibuprofen Analgesics

Arm

Intervention/Treatment

Active Comparator: INF + HM

The participant will receive a dose of intranasal fentanyl (1.5 mcg/kg up to a maximum of 100 mcg) AND a dose of oral hydromorphone (0.04mg/kg up to a maximum of 2 mg).

Drug: Fentanyl intranasal + Oral Hydromorphone

Analgesics

Active Comparator: INF + IBU

The participant will receive a dose of intranasal (1.5 mcg/kg up to a maximum of 100 mcg) AND a dose of oral ibuprofen (10 mg/kg up to a maximum of 600 mg)

Drug: Fentanyl intranasal + Oral ibuprofen

Analgesics

Outcome Measures

Primary Outcome Measures

Proportion of children in each group with a pain intensity score <30 mm at 60 minutes post-medication administration [60 minutes post-medication administration (T-60)]
Measure: Visual Analogue Scale (VAS)

Secondary Outcome Measures

Mean pain scores [Time of the administration of medication (T-0), 10 min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during the medical examination (T-ME), and during radiographic procedure (T-XR)]
Measure: Visual Analogue Scale (VAS)
Proportion of children administered a rescue analgesic [Within 60 minutes following administration of study medication]
Proportion of children with side effects [10 min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during the medical examination (T-ME), and during radiographic procedure (T-XR), 24 hours post-discharge from the ED]
At each assessment points, the research nurse will evaluate the presence of side effects (clinical data)
Proportion of children in each group with an RSS score between 1 to 3 [10 min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during the medical examination (T-ME), and during radiographic procedure (T-XR)]
At each assessment points, the research nurse will evaluate the child's sedation level using the Ramsay Sedation Scale (RSS)
Parental and child reports of acceptability of the medication [120 min (T-120) after medication administration]
Dichotomized question (yes/no) on the acceptability of the medication
Self-reported levels of satisfaction of children and parents with pain management [120 min (T-120) after medication administration]
Dichotomized question (yes/no) on the levels of satisfaction of children and parents with pain management
Mean differences in pain scores (between groups) [Time of the administration of medication (T-0), 10 min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during the medical examination (T-ME), and during radiographic procedure (T-XR)]
Measure: Visual Analogue Scale (VAS)
Occurence of Serious adverse events [10min (T-10), 20 min (T-20), 30 min (T-30), 60 min (T-60), 90 min (T-90), 120 min (T-120) after medication administration, during medical examination (T-ME) and during radiographic procedure (T-XR)]
Checklist of Serious Adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

pain score >49 mm on the VAS at triage
between the ages of 8 and 17 years
presenting to the ED with a suspected fracture of the upper of lower limb
who can communicate in either French or English

Exclusion Criteria:

known allergy to fentanyl, hydromorphone, ibuprofen, or artificial colouring
triage nurse suspicion of child abuse
inability to self-report pain
chronic pain that necessitates daily analgesic use
NSAID or opioid use within the three hours prior to ED presentation
trauma to >1 limb
known hepatic or renal disease/dysfunction
known bleeding disorder
neuro-cognitive disability that precludes assent and/or participating in the study
known history of obstructive sleep apnea
a suspected fracture of the nose
significant head injury, as determined by the clinical team/triage nurse.