PainPhase 3PRIMENCT02778880
Pain Reduction With Intranasal Medications for Extremity Injuries
A Phase 3 study testing Ketamine and Fentanyl in people with Pain and Traumatic Limb Injury, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
Trial summary
This study compares the analgesic effect of intranasal sub-dissociative dosing of ketamine and intranasal fentanyl in children presenting to the Emergency Department with acute extremity injuries. Read more about this study
- Who is it for?
- Ages 8 to 17 years
- Conditions the study is for
- Pain, Traumatic Limb Injury
- What is being tested?
- Ketamine and Fentanyl
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Mar 2016to 21 Mar 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 8 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 8 years to 17 years (up to the 18th birthday)
- Presenting to emergency department with one or more extremity injuries
- Visual analog scale score 35 mm or greater
- Parent or legal guardian present and willing to provide written consent
Who cannot join
- Received narcotic pain medication prior to arrival
- Evidence of significant head, chest, abdomen, or spine injury
- Glasgow coma score less than 15 or unable to self report pain score
- Nasal trauma or aberrant nasal/airway anatomy
- Active epistaxis
- Allergy to ketamine, fentanyl or meperidine
Show all 11Show fewer
- Non-English speaking parent and/or child
- History of psychosis
- Postmenarchal female without a urine or serum assay documenting the absence of pregnancy
- Brought in my juvenile detention center or in police custody
- Pregnancy
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
About this study
Official title: A Randomized Controlled Trial of Intranasal Sub-dissociative Dosing of Ketamine Compared to Intranasal Fentanyl for Treatment of Pain Associated With Acute Extremity Injuries in Children
This study compares the analgesic effect of intranasal sub-dissociative dosing of ketamine and intranasal fentanyl in children presenting to the Emergency Department with acute extremity injuries.
Read the detailed description
Inadequate pain control, especially in the emergency department (ED), is a major public health concern. Despite increased awareness, pain continues to be underdiagnosed and undertreated, particularly in the pediatric population. Children often encounter long delays in medication administration, possibly due to the time required to obtain intravenous access. The intranasal administration route offers a more efficient alternative for faster and noninvasive delivery of pain medication. This route is gaining popularity secondary to its rapid onset of active, minimal discomfort and relative simplicity.
Opioids are the most commonly used class of analgesic pain medication for children presenting in severe pain due to traumatic injuries. Despite their potential effectiveness, opioids have several concerning adverse effects, particularly when administered prior to procedural sedation in children. Administration of pre-procedural sedation opioids is associated with an increased risk of serious adverse events (oxygen desaturation, apnea, and hypotension) as well as the need for significant interventions, such as bag-mask ventilation, intubation, and pharmacologic blood pressure support. In addition, due to genetic variations that may lead to increased or diminished opioid sensitivity, ideal dosing to adequately control severe pain yet avoid adverse medication-related side effects is difficult to ascertain. Many children in severe pain do not receive opioids, receive doses that are below those recommended or experience long delays in receiving opioids. The reasons for this are unclear, but the investigators speculate that this may be due in part to fear of adverse effects of opioids, provider inexperience with opioid use in children or fear of contributing to opioid tolerance or abuse. For all of these reasons, providers often seek non-opioid alternatives for pediatric patients with acute, severe pain.
Ketamine, in sub-dissociative doses administered by the intravenous or intranasal route, is emerging as an alternative medication for the treatment of moderate to severe pain in multiple settings. In adults, low dose ketamine is well tolerated and has been used successfully as an adjuvant and an alternative to opioids to provide rapid pain relief in the ED. As a dissociative anesthetic, ketamine is the most commonly used agent to facilitate painful procedures in the pediatric emergency department. At lower doses, it has been used in children to provide analgesia in a variety of acute and chronic pain settings, including terminal diagnoses, sickle cell disease, perioperative pain, traumatic injuries, extensive burns and conditions where opioids are contraindicated. Similar to adults, ketamine has been used via the intranasal route to provide adequate analgesia and sedation in children in the pre-hospital setting and in those undergoing procedures.
The objective of this study is to compare intranasal sub-dissociative ketamine with intranasal fentanyl for treatment of acute pain associated with traumatic limb injuries in children presenting to the ED and to document an objective respiratory side effect profile utilizing noninvasive capnometry. If found to be an effective analgesic, intranasal ketamine would be particularly useful in children who experience adverse effects with opioids, have developed opioid tolerance as a result of chronic painful conditions, have poor opioid sensitivity due to their genetic predisposition or in pediatric trauma patients with the potential for hypotension. Additionally, for patients that require procedural sedation for fracture reduction, avoiding opioids early in the emergency department visit may decrease sedation recovery time and the risk of serious adverse events during sedation.
- Conditions
- Pain, Traumatic Limb Injury
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Ketamine | Experimental | Ketamine 1.5 mg/kg intranasally for one dose Receives: Drug: Ketamine |
| Fentanyl | Active comparator | Fentanyl 2 mcg/kg intranasally for one dose Receives: Drug: Fentanyl |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Measured: 30 minutes after study medication
Secondary outcomes (22)
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Measured: 15 minutes after study medication
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Measured: 60 minutes after study medication
Highest Achieved University of Michigan Sedation Scale (UMSS) Score
The University of Michigan Sedation Scale is a valid and reliable tool that allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that assesses the level of alertness on a five-point scale. It has been validated in children and has shown to have significant inter-rater reliability. Score is 0-4 (0 = awake and alert; 1= minimally sedated; 2 = moderately sedated; 3 = deeply sedated; 4 = unarousable)
Measured: 15, 30, and 60 minutes after study medication administration
Rescue Analgesia
Documentation of additional pain medication after study medication administration
Measured: Within the first 60 minutes after study medication
Heart Rate
Measured: 15 minutes after study medication
Heart Rate
Measured: 30 minutes after study medication
Heart Rate
Measured: 60 minutes after study medication
Respiratory Rate
Measured: 15 minutes after study medication
Respiratory Rate
Measured: 30 minutes after study medication
Respiratory Rate
Measured: 60 minutes after study medication
Systolic Blood Pressure
Measured: 15 minutes after study medication
Systolic Blood Pressure
Measured: 30 minutes after study medication
Systolic Blood Pressure
Measured: 60 minutes after study medication
Diastolic Blood Pressure
Measured: 15 minutes after study medication
Diastolic Blood Pressure
Measured: 30 minutes after study medication
Diastolic Blood Pressure
Measured: 60 minutes after study medication
Oxygen Saturation
Measured: 15 minutes after study medication
Oxygen Saturation
Measured: 30 minutes after study medication
Oxygen Saturation
Measured: 60 minutes after study medication
Capnometry Value
Measured: 15 minutes after study medication
Capnometry Value
Measured: 30 minutes after study medication
Capnometry Value
Measured: 60 minutes after study medication
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2016 (estimated)
- Study start31 Mar 2016
- Primary completion22 Feb 2017
- Study completion21 Mar 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe sponsor's other registered studies.
- 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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Theresa M Frey, MD, Principal investigator, Children's Hospital Medical Center, CincinnatiMatthew R Mittiga, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02778880
- Sponsor's protocol ID
- CIN_PRIME_001
- Acronym
- PRIME
- Status last verified
- Oct 2018
- First submitted
- 19 Apr 2016
- Last updated
- 1 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Frey TM, Florin TA, Caruso M, Zhang N, Zhang Y, Mittiga MR. Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatr. 2019 Feb 1;173(2):140-146. doi: 10.1001/jamapediatrics.2018.4582.
PubMed 30592476
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled Trial of Intranasal Sub-dissociative Dosing of Ketamine Compared to Intranasal Fentanyl for Treatment of Pain Associated With Acute Extremity Injuries in Children
- ClinicalTrials.gov ID
- NCT02778880
- Acronym / sponsor ID
- PRIME / CIN_PRIME_001
- Conditions
- Pain, Traumatic Limb Injury
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Study start
- 31 Mar 2016 (actual)
- Primary completion
- 22 Feb 2017 (actual)
- Study completion
- 21 Mar 2017 (actual)
- First posted
- 20 May 2016 (estimated)
- Results
- Posted 1 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study compares the analgesic effect of intranasal sub-dissociative dosing of ketamine and intranasal fentanyl in children presenting to the Emergency Department with acute extremity injuries.
Detailed description
Inadequate pain control, especially in the emergency department (ED), is a major public health concern. Despite increased awareness, pain continues to be underdiagnosed and undertreated, particularly in the pediatric population. Children often encounter long delays in medication administration, possibly due to the time required to obtain intravenous access. The intranasal administration route offers a more efficient alternative for faster and noninvasive delivery of pain medication. This route is gaining popularity secondary to its rapid onset of active, minimal discomfort and relative simplicity.
Opioids are the most commonly used class of analgesic pain medication for children presenting in severe pain due to traumatic injuries. Despite their potential effectiveness, opioids have several concerning adverse effects, particularly when administered prior to procedural sedation in children. Administration of pre-procedural sedation opioids is associated with an increased risk of serious adverse events (oxygen desaturation, apnea, and hypotension) as well as the need for significant interventions, such as bag-mask ventilation, intubation, and pharmacologic blood pressure support. In addition, due to genetic variations that may lead to increased or diminished opioid sensitivity, ideal dosing to adequately control severe pain yet avoid adverse medication-related side effects is difficult to ascertain. Many children in severe pain do not receive opioids, receive doses that are below those recommended or experience long delays in receiving opioids. The reasons for this are unclear, but the investigators speculate that this may be due in part to fear of adverse effects of opioids, provider inexperience with opioid use in children or fear of contributing to opioid tolerance or abuse. For all of these reasons, providers often seek non-opioid alternatives for pediatric patients with acute, severe pain.
Ketamine, in sub-dissociative doses administered by the intravenous or intranasal route, is emerging as an alternative medication for the treatment of moderate to severe pain in multiple settings. In adults, low dose ketamine is well tolerated and has been used successfully as an adjuvant and an alternative to opioids to provide rapid pain relief in the ED. As a dissociative anesthetic, ketamine is the most commonly used agent to facilitate painful procedures in the pediatric emergency department. At lower doses, it has been used in children to provide analgesia in a variety of acute and chronic pain settings, including terminal diagnoses, sickle cell disease, perioperative pain, traumatic injuries, extensive burns and conditions where opioids are contraindicated. Similar to adults, ketamine has been used via the intranasal route to provide adequate analgesia and sedation in children in the pre-hospital setting and in those undergoing procedures.
The objective of this study is to compare intranasal sub-dissociative ketamine with intranasal fentanyl for treatment of acute pain associated with traumatic limb injuries in children presenting to the ED and to document an objective respiratory side effect profile utilizing noninvasive capnometry. If found to be an effective analgesic, intranasal ketamine would be particularly useful in children who experience adverse effects with opioids, have developed opioid tolerance as a result of chronic painful conditions, have poor opioid sensitivity due to their genetic predisposition or in pediatric trauma patients with the potential for hypotension. Additionally, for patients that require procedural sedation for fracture reduction, avoiding opioids early in the emergency department visit may decrease sedation recovery time and the risk of serious adverse events during sedation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ketamine | Experimental | Drug: KetamineKetamine 1.5 mg/kg intranasally for one dose |
| Fentanyl | Active comparator | Drug: FentanylFentanyl 2 mcg/kg intranasally for one dose |
Who may qualify
- Ages
- 8 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 8 years to 17 years (up to the 18th birthday)
- Presenting to emergency department with one or more extremity injuries
- Visual analog scale score 35 mm or greater
- Parent or legal guardian present and willing to provide written consent
Key exclusion criteria (11 listed)
- Received narcotic pain medication prior to arrival
- Evidence of significant head, chest, abdomen, or spine injury
- Glasgow coma score less than 15 or unable to self report pain score
- Nasal trauma or aberrant nasal/airway anatomy
- Active epistaxis
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 |
|---|---|---|
| KetamineAlso: Ketalar | Drug | Ketamine |
| Fentanyl | Drug | Fentanyl |
Primary outcome
Difference From Baseline in Visual Analog Scale Pain Score
Time frame: 30 minutes after study medication
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
22 secondary outcomes
Difference From Baseline in Visual Analog Scale Pain Score
Time frame: 15 minutes after study medication
Difference From Baseline in Visual Analog Scale Pain Score
Time frame: 60 minutes after study medication
Highest Achieved University of Michigan Sedation Scale (UMSS) Score
Time frame: 15, 30, and 60 minutes after study medication administration
Rescue Analgesia
Time frame: Within the first 60 minutes after study medication
Heart Rate
Time frame: 15 minutes after study medication
Heart Rate
Time frame: 30 minutes after study medication
Heart Rate
Time frame: 60 minutes after study medication
Respiratory Rate
Time frame: 15 minutes after study medication
Respiratory Rate
Time frame: 30 minutes after study medication
Respiratory Rate
Time frame: 60 minutes after study medication
Systolic Blood Pressure
Time frame: 15 minutes after study medication
Systolic Blood Pressure
Time frame: 30 minutes after study medication
Systolic Blood Pressure
Time frame: 60 minutes after study medication
Diastolic Blood Pressure
Time frame: 15 minutes after study medication
Diastolic Blood Pressure
Time frame: 30 minutes after study medication
Diastolic Blood Pressure
Time frame: 60 minutes after study medication
Oxygen Saturation
Time frame: 15 minutes after study medication
Oxygen Saturation
Time frame: 30 minutes after study medication
Oxygen Saturation
Time frame: 60 minutes after study medication
Capnometry Value
Time frame: 15 minutes after study medication
Capnometry Value
Time frame: 30 minutes after study medication
Capnometry Value
Time frame: 60 minutes after study medication
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30592476Frey TM, Florin TA, Caruso M, Zhang N, Zhang Y, Mittiga MR. Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatr. 2019 Feb 1;173(2):140-146. doi: 10.1001/jamapediatrics.2018.4582.
- Individual participant dataSharing planned: No
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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.
Theresa M Frey, MD principal investigator
Children's Hospital Medical Center, Cincinnati
Matthew R Mittiga, MD principal investigator
Children's Hospital Medical Center, Cincinnati
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 Ketamine and Fentanyl in people with Pain and Traumatic Limb Injury, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
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 4 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 1 Sep 2020. 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 United States. 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?
Yes. Results are posted in the registry (first posted 1 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Difference From Baseline in Visual Analog Scale Pain Score (time frame: 30 minutes after study medication). 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 NCT02778880, 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 1 Sep 2020.