IN Sub-Dissociative Ketamine vs IN Fentanyl

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT02521415
• Collaborator: Carolinas Trauma Network Research Group (Other), Charlotte, Houston, Milwaukee Prehospital Emergency Research Nodal Center-CHaMP-ERNC (Other)
• Enrollment: 87
• Location: 1
• Arms: 2
• Duration (Months): 11
• Patients Per Site Per Month: 7.9

Study Details

Study Description

Brief Summary

This single center, randomized control, double blind trial will prospectively examine the feasibility of intranasal, sub-dissociative (IN) ketamine versus intranasal fentanyl for pain control in the pediatric emergency department setting. The investigators hypothesize that IN ketamine may provide a safe and effective alternative to IN fentanyl for children with suspected, isolated extremity fractures.

Eighty children ages 3-17 years with a suspected, isolated extremity fracture that requires analgesia will be randomized to receive IN ketamine or IN fentanyl upon presentation to the emergency department and will be followed for 2 hours for efficacy and 6 hours for safety.

Condition or Disease	Intervention/Treatment	Phase
Bone Fracture	Drug: ketamine; Drug: fentanyl; Drug: ibuprofen or acetaminophen	Phase 2

Detailed Description

Intranasal medications are commonly used in place of parenteral opioids in children. IN fentanyl is the most commonly used intranasal analgesic medication in the pediatric population with demonstrated safety and efficacy comparable to IV fentanyl and IV morphine. IN ketamine, at sub-dissociative doses, offers similar safety and efficacy to IN fentanyl and the additional advantage of potentially reducing the total use of opioid agents during the emergency department visit. Ketamine is easily stored and has a wide therapeutic window with an extremely low risk of cardiorespiratory complications. This study will compare the safety and efficacy of IN ketamine to IN fentanyl in children with suspected, isolated extremity fractures in the pediatric emergency department.

The primary aim of the study is to examine the feasibility of future protocol expansion. The investigators will conclude that additional studies are NOT feasible if the observed rate of side effects for ketamine that exceeds fentanyl by three-fold or event rate of 5% or more for ketamine-related SAEs. The primary aim of the study will compare the frequency of adverse events over 6-hours among children randomized to receive either intranasal sub-dissociative ketamine (IN ketamine) or intranasal fentanyl (IN fentanyl) for pain control in the emergency department. The exploratory aim of the study will compare the efficacy of intranasal ketamine to intranasal fentanyl as measured by a reduction in age appropriate pain scale scores over 2-hours. The secondary aim of the study will compare the total dose of opioid pain medication in morphine equivalents/kg/hour required during the ED evaluation of children with suspected, isolated extremity fractures after randomization and treatment with IN ketamine or IN fentanyl.

Eighty children ages 3-17 years with a suspected, isolated extremity fracture that requires analgesia will be randomized to receive IN ketamine or IN fentanyl upon presentation to the emergency department and will be followed for 2 hours for efficacy and 6 hours for safety.

All participants will be premedicated with acetaminophen or ibuprofen and baseline data, including pain level, will be collected. The trial consists of two treatment arms. (IN ketamine 1 mg/kg or IN fentanyl 1.5 mcg/kg). Randomization will follow a 1:1 ratio, with approximately 40 per group. Randomization will be stratified by ages 3-10 and 11-17. The participants will be assessed by a research coordinator for adverse events every 5 minutes using an adverse events checklist for the first fifteen minutes post study medication administration and every 30 minutes for the first two hours after drug administration. The vital signs and pain scale assessment will be repeated every 10 minutes for the first 30 minutes and then every 30 minutes for the first two hours after drug administration. A final assessment will be made 6 hours after the last dose of study drug or at discharge from the ED to assess for late side effects or adverse events. Study medication may be repeated times one at a reduced dose after 20 minutes when the full effects of the first dose are known. The decision to administer additional study medication (0.5 mg/kg ketamine or 0.75 mcg/kg fentanyl ) will at be at the discretion of the treating physician. Should a second dose of study medication be required, a new schedule of patient assessments will commence following the same schedule as for the first dose. Participant assessments will continue until the 2 hour endpoint is reached from the time of the last drug administration, with a final assessment at 6 hours after the last dose of study drug or at discharge from the ED to assess for late side effects or adverse events.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Controlled Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children With Suspected, Isolated Extremity Fractures in the Pediatric Emergency Department
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ketamine ketamine (1mg/kg)	Drug: ketamine; intranasal (IN) sub-dissociative ketamine (1mg/kg); Other Names: intranasal pain medication ; Drug: ibuprofen or acetaminophen; 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Active Comparator: fentanyl fentanyl (1.5 micrograms/kg)	Drug: fentanyl; Intranasal (IN) fentanyl (1.5 micrograms/kg); Other Names: intranasal pain medication ; Drug: ibuprofen or acetaminophen; 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention

Outcome Measures

Primary Outcome Measures

1. Primary Outcome: Number of Participants With Minor Side Effects and Significant Adverse Events [60 minutes]

   We will conclude that such a study is NOT feasible if we observe a rate of side effects for ketamine that exceeds fentanyl by three-fold or event rate of 5% or more for ketamine-related significant adverse events. Side effects are common events experienced by patients receiving ketamine or fentanyl that do not change outcomes for the patient but may affect the patient experience. A significant adverse event (SAE) includes any adverse event that begins after the short form consent has been completed that causes a threat to life, limb or an organ system, causes prolongation of hospitalization, or requires new medical or surgical treatment to correct.

Secondary Outcome Measures

1. Secondary Outcome: Total Dose of Opioid Pain Medication in Morphine Equivalents/kg/Hour [participants will be followed during the emergency department length of stay, estimated to average 6 hours]

   Compare the total dose of opioid pain medication in morphine equivalents/kg/hour required during the ED evaluation of children with suspected forearm fractures after randomization and treatment with IN ketamine or IN fentanyl.

Other Outcome Measures

1. Exploratory Outcome: Reduction in Age Appropriate Pain Scale Scores [20 minutes]

   Mean difference in the reduction of the pain scale scores at 20 minutes. Two commonly used, age appropriate and previously validated, pediatric pain assessment tools were used: FACES Pain Scale - Revised for children ages 4-10 and the Visual Analog Scale for children ages 11-17. The FACES Pain Scale - Revised is a self-reported measure of pain intensity developed for children with pain intensity represented by images of grimacing faces on a scale of 0 (no pain) to 10 (maximum pain). The Visual Analog Scale is a self-reported measure of pain intensity where patients mark their pain level on a 10 cm line that represents a continuum of no pain at 0 cm and worst pain at 10 cm. For analysis, pain scale data were merged and reported as values form 0 to 100. The minimum clinically significant reduction in pain was defined as a decrease of 20.

2. Secondary Safety Outcome: Adverse Events Over 6 Hours [6 hours]

   Compare the frequency of types of adverse events over 6-hours among children randomized to receive either intranasal sub-dissociative ketamine (IN ketamine) or intranasal fentanyl (IN fentanyl) for pain control in the emergency department.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• single suspected, isolated extremity fracture that requires analgesia

Exclusion Criteria:

• GCS < 15 at ED presentation,

• reported allergy or adverse reaction to ketamine or fentanyl,

• pregnancy,

• intoxication,

• hypotension (less than 70 mmHg +2x age or less than 90 mm Hg for patients greater than 11 years of age)

• weight > 70 kg

• patients receiving opioid analgesia administered prior to arrival

• multiply injured patients (injuries to multiple extremities)

• aberrant nasal anatomy that precludes IN medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carolinas Medical Center Main - Levine Children's Hospital Emergency Department	Charlotte	North Carolina	United States	28203

Sponsors and Collaborators

• Wake Forest University Health Sciences
• Carolinas Trauma Network Research Group
• Charlotte, Houston, Milwaukee Prehospital Emergency Research Nodal Center-CHaMP-ERNC

Investigators

• Principal Investigator: Stacy Reynolds, MD, Carolinas Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02521415
• Other Study ID Numbers: INK-2015
• First Posted: Aug 13, 2015
• Last Update Posted: Jul 26, 2022
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Fractures, Bone; Acetaminophen; Ibuprofen; Fentanyl; Ketamine; Analgesics

Study Results

Participant Flow

Arm/Group Title	Ketamine	Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Period Title: Overall Study
STARTED	43	44
COMPLETED	43	44
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ketamine	Fentanyl	Total
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	Total of all reporting groups
Overall Participants	43	44	87
Age, Customized (Count of Participants)
4-10 years	30 69.8%	32 72.7%	62 71.3%
11-17 years	13 30.2%	12 27.3%	25 28.7%
Sex: Female, Male (Count of Participants)
Female	17 39.5%	16 36.4%	33 37.9%
Male	26 60.5%	28 63.6%	54 62.1%
Race/Ethnicity, Customized (Count of Participants)
African American/black	10 23.3%	8 18.2%	18 20.7%
White	22 51.2%	26 59.1%	48 55.2%
American Indian/Alaskan native	1 2.3%	0 0%	1 1.1%
Other	10 23.3%	10 22.7%	20 23%
Hispanic or Latino	7 16.3%	12 27.3%	19 21.8%
Not Hispanic or Latino	35 81.4%	32 72.7%	67 77%
Unknown	1 2.3%	0 0%	1 1.1%
Region of Enrollment (Count of Participants)
United States	43 100%	44 100%	87 100%

Outcome Measures

1. Primary Outcome

Title	Primary Outcome: Number of Participants With Minor Side Effects and Significant Adverse Events
Description	We will conclude that such a study is NOT feasible if we observe a rate of side effects for ketamine that exceeds fentanyl by three-fold or event rate of 5% or more for ketamine-related significant adverse events. Side effects are common events experienced by patients receiving ketamine or fentanyl that do not change outcomes for the patient but may affect the patient experience. A significant adverse event (SAE) includes any adverse event that begins after the short form consent has been completed that causes a threat to life, limb or an organ system, causes prolongation of hospitalization, or requires new medical or surgical treatment to correct.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Measure Participants	43	44
serious adverse events	0 0%	0 0%
non-serious adverse events	41 95.3%	25 56.8%
no AEs observed	2 4.7%	19 43.2%

2. Secondary Outcome

Title	Secondary Outcome: Total Dose of Opioid Pain Medication in Morphine Equivalents/kg/Hour
Description	Compare the total dose of opioid pain medication in morphine equivalents/kg/hour required during the ED evaluation of children with suspected forearm fractures after randomization and treatment with IN ketamine or IN fentanyl.
Time Frame	participants will be followed during the emergency department length of stay, estimated to average 6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Measure Participants	43	44
Median (Inter-Quartile Range) [morphine equivalents/kg/hr]	0.04	0.05

3. Other Pre-specified Outcome

Title	Exploratory Outcome: Reduction in Age Appropriate Pain Scale Scores
Description	Mean difference in the reduction of the pain scale scores at 20 minutes. Two commonly used, age appropriate and previously validated, pediatric pain assessment tools were used: FACES Pain Scale - Revised for children ages 4-10 and the Visual Analog Scale for children ages 11-17. The FACES Pain Scale - Revised is a self-reported measure of pain intensity developed for children with pain intensity represented by images of grimacing faces on a scale of 0 (no pain) to 10 (maximum pain). The Visual Analog Scale is a self-reported measure of pain intensity where patients mark their pain level on a 10 cm line that represents a continuum of no pain at 0 cm and worst pain at 10 cm. For analysis, pain scale data were merged and reported as values form 0 to 100. The minimum clinically significant reduction in pain was defined as a decrease of 20.
Time Frame	20 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Measure Participants	43	44
Mean (Standard Deviation) [units on a scale]	44 (36)	35 (29)

4. Other Pre-specified Outcome

Title	Secondary Safety Outcome: Adverse Events Over 6 Hours
Description	Compare the frequency of types of adverse events over 6-hours among children randomized to receive either intranasal sub-dissociative ketamine (IN ketamine) or intranasal fentanyl (IN fentanyl) for pain control in the emergency department.
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

Data were collected but all secondary outcomes for the study have not yet been analyzed

Arm/Group Title	Ketamine	Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention	fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
Measure Participants	0	0

Adverse Events

Time Frame	Hour 6
Arm/Group Title	Ketamine		Fentanyl
Arm/Group Description	ketamine (1mg/kg) ketamine: intranasal (IN) sub-dissociative ketamine (1mg/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention		fentanyl (1.5 micrograms/kg) fentanyl: Intranasal (IN) fentanyl (1.5 micrograms/kg) ibuprofen or acetaminophen: 10 mg/kg of ibuprofen or 15 mg/kg of acetaminophen will be given to participants prior to the randomized intervention
All Cause Mortality
	Ketamine		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/43 (0%)		0/44 (0%)
Serious Adverse Events
	Ketamine		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/43 (0%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/43 (95.3%)		25/44 (56.8%)
Eye disorders
visual disturbance	4/43 (9.3%)	4	1/44 (2.3%)	1
Gastrointestinal disorders
nausea	3/43 (7%)	3	3/44 (6.8%)	3
General disorders
any adverse event	41/43 (95.3%)	41	25/44 (56.8%)	25
bad taste in mouth/throat	37/43 (86%)	37	9/44 (20.5%)	9
sleepiness	19/43 (44.2%)	19	15/44 (34.1%)	15
drowsiness	6/43 (14%)	6	3/44 (6.8%)	3
itchy nose	10/43 (23.3%)	10	9/44 (20.5%)	9
dysphoria	1/43 (2.3%)	1	2/44 (4.5%)	2
Nervous system disorders
dizziness	30/43 (69.8%)	30	6/44 (13.6%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.