RCT: Fentanyl Plus Ketamine Versus Fentanyl Alone for Acute Burn Pain

Study Overview
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Brief Summary
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The Ketamine for Acute Pain in Burns study is a randomized, double-blind, parallel group trial (RCT) with active control (usual care) contrasting the efficacy and safety of Ketamine Plus Opiate-based usual care (O+K) with the safety and efficacy of the Current Standard of Care. THe current standard of care is an opiate medication alone, Fentanyl (Usual Care-Opiate (UC-O), dose/timing as per Burn Center protocol).

Detailed Description
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Department of Defense (DoD) and the U.S. Army Medical Research and Materiel Command (USAMRMC) are funding this RCT for the following reasons: Primary Aims: To evaluate the safety and efficacy of fentanyl (usual care) + placebo versus fentanyl + ketamine (low-dose, sub-anesthetic, slow-infusion) during twice daily burn wound care across a 7-day study period and 30 day outcome period. To evaluate the opiate sparing effect of fentanyl (usual care) + placebo versus fentanyl + ketamine (low-dose, sub-anesthetic, slow-infusion) during the 7-day study period and 30 day outcome period. and Secondary Aims: To determine the short and long term effect of the Ketamine Augmentation Condition versus the Usual Care Condition on symptoms and syndromes of posttraumatic stress disorder and of depression, To evaluate several established and hypothesized moderators of the relationship between the Ketamine Augmentation Condition versus the Usual Care Condition on: 1) pain severity reported during wound care, 2) opiate use during wound care, 3) posttraumatic stress and 4) depression.

Official Title
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Evaluating the Safety, Efficacy and Opiate Sparing Effects of Low-Dose, Slow Infusion Ketamine as a Battlefield Analgesic for Acute Pain in Burn Wounds.

Conditions
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Acute Pain, Wound Care, Posttraumatic Stress Disorder

Intervention / Treatment
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* Drug: ketamine
* Drug: Fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Total Body Surface Area (TBSA) greater than or equal to 2%; Less than or equal to 40% TBSA English speaking pain in emergency room during initial wound evaluation (on admission) greater than 5 /10 estimated length of stay greater than or equal to 5 days Exclusion Criteria: requiring endotracheal intubation and sedation, severe hearing impairment, cognitive impairment status - Mini-Mental State Examination (MMSE) </=20, diminished capacity unable to provide informed consent; Past Medical History (PMH): insensate (eg. spinal cord injury, peripheral neuropathy) Safety: contraindication (e.g., potential drug interactions or medical comorbidities)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, repeated exposure (twice daily, 7 days), safety and efficacy trial of Usual Care (fentanyl PLUS saline / placebo) versus Usual Care plus Study Drug Augmentation (fentanyl PLUS ketamine) in reducing acute pain severity assessed before, during and after wound care for acute burn injury in the Burn Center of an Academic Medical Center.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fentanyl Plus Ketamine<br>Study drug group Ketamine Loading Dose (Low Dose, Slow Infusion) = • 0.3 mg/kg; Initiated approximately 10 minutes before wound care start, pump set to deliver slowly over approximately 5 minutes, … Then, Fentanyl Loading Dose (UC, injection) = • 1 mcg / kg. This is given to participants in both Group 1 and Group 2 initiated < 1 minute prior to wound care. Ketamine (Study Drug, Infusion) = • 2.5 mcg/kg/min, Pump initiates infusion immediately after the fentanyl Loading Dose and continued for session duration. The nurse determines session end, then turns off infusion. Fentanyl PRN dose* = 1 mcg / kg. Provided when participant requires additional pain medication. | Drug: ketamine<br>* Information included in arm descriptions<br>* Other names: STUDY DRUG GROUP (Fentanyl plus Ketamine);Drug: Fentanyl<br>* Information included in arm descriptions<br>* Other names: USUAL CARE GROUP (Fentanyl plus saline/placebo);|
| Active Comparator: Fentanyl Plus Saline<br>Usual care group Saline Loading Dose (Low Dose, Slow Infusion) = • An identical volume of saline as that in 0.3 mg/kg of ketamine. Initiated approximately 10 minutes before wound care start, pump set to deliver slowly over approximately 5 minutes, (i.e., same time/rate as STUDY DRUG GROUP receives ketamine loading dose), … Then, ... Fentanyl Loading Dose (UC, injection) = • 1 mcg / kg: This is given to participants in both Group 1 and Group 2 initiated <1 minute prior to wound care. Saline (Placebo, Infusion) = • Identical volume of fluid as that in 2.5 mcg/kg/min of ketamine; Pump initiates infusion immediately after the fentanyl Loading Dose and continued for session duration. The nurse determines session end, then turns off infusion. FENTANYL PRN DOSE = 1 mcg / kg. Provided when participant requires additional pain medication. | Drug: Fentanyl<br>* Information included in arm descriptions<br>* Other names: USUAL CARE GROUP (Fentanyl plus saline/placebo);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Wound Care Pain | Average Pain across 14 sessions between the 2 groups and related outcome measures up to 40 days following study enrollment. | Up to 40 days | 
| Trajectory of Mean Wound Care Session Pain Within Sessions | Trajectory of average pain within session | 7-days, within session | 
| Trajectory of Mean Wound Care Session Pain Across Sessions | Trajectory of average pain across 7 day study protocol | 7-Days across sessions | 
| Opiate Sparing Effect | Pro Re Nata (PRN) pain management or adjunct expressed in opiate equivalents (e.g., anxiolytic) or premed (e.g., non-protocol medications for pain, anxiety, etc); post-session (1 and 6 hours post session , e.g., pain, anxiolytic, etc). | 37 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post Traumatic Stress Disorder (PTSD) Symptoms as Assessed by Davidson Trauma Scale | PTSD symptoms score as assessed by Davidson Trauma Scale consisting of 17 items (symptoms) with each item measured for severity and frequency. Each item is rated 0 - 4. Overall score ranges from 0 to 136, with higher scores indicating higher frequency and severity. | 37 days | 
| Depression Symptoms as Assessed by the Patient Health Questionnaire | Severity and trajectory of depression symptoms as assessed by the Patient Health Questionnaire (PHQ) 9. The questionnaire has 9 items with each rated from 0 to 3. Overall scores ranges from 0 to 27 with 1-4 being minimal depression, 5-9 being mild depression, 10-14 being moderate depression, 15-19 being moderately severe depression and 20-27 being severe depression. | 37 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opioid, ketamine