Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain

NCT02866071 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: McMullan Ketamine
• Study Type: interventional
• Target: 224
• Locations: 1 country
• Sites: 1

Brief Summary

STUDY SYNOPSIS Objectives The primary objective is to estimate the proportion of subjects who report clinically important reductions in pain score (defined as 2 points on a 0-10 verbal numerical rating scale) after receiving a single dose of fentanyl (per local standard) with or without intranasal (IN) ketamine (50mg) prior to hospital arrival for the treatment of acute traumatic pain. Design and Outcomes This protocol describes two linked studies conducted as a prospective, randomized, placebo-controlled single-site clinical trial. The primary study has a primary outcome variable of reduction of reported pain of at least 2 points (on the 0-10 Verbal Numerical Rating Scale1,2) when comparing the pretreatment pain score to the pain score obtained upon reassessment 30 minutes after medication administration; secondary outcomes of the primary trial include reduction of reported pain at Emergency Department (ED) arrival; the incidence of adverse events; additional opiate requirements prior to ED arrival and in the first three hours of ED care. The secondary study explores secondary outcomes including: development of chronic pain (measured by the Brief Pain Inventory,3) or post-traumatic stress disorder (measured by the PTSD Checklist for DSM-54) and overall satisfaction with life (measured by the Satisfaction With Life Scale5) at 90-days after injury. Interventions and Duration Adult men who qualify for prehospital pain treatment under paramedic standing orders will be screened for inclusion and will undergo informed consent for the primary trial. After ED arrival, subjects who consented for the primary trial will be approached for inclusion in the secondary trial. Prehospital consent for primary trial enrollment and study drug administration will occur concurrent with receiving a single dose of fentanyl (IV, IM or IN per current standard practice). Consenting subjects will be 1:1 randomized to receive either 50mg IN ketamine or IN saline placebo. Pain will be rated on a 0-10 scale by the subject prior to treatment and at 30 minutes following treatment and will receive further pain assessments at 30 minute intervals for the first three hours of their ED care. Additional pain medications given prior to hospital arrival and within the first three hours of ED care will also be recorded. The primary outcome of the primary trial will be reduction in baseline pain between the pretreatment measurement and 30 minutes after medication administration. Consent for the secondary trial will be obtained for the additional baseline assessments for secondary outcomes and at 90-day follow-up. Overall satisfaction with life and symptoms of PTSD and chronic pain will be assessed before hospital disposition (in-person) and via phone follow-up at 90-days (+/- 14 days) after injury.The subject will have the option to complete the 90-day follow-up assessments in-person if it coincides with a clinical appointment on the medical campus. Sample size and Power We consider a 2-point reduction in pain to be clinically significant, and thus our primary outcome for the primary trial will compare the proportion of subjects achieving a 2-point reduction in pain at 30 minutes post-medication administration between the treatment group and the control group. Sample size considerations are based on this primary analysis. To test the hypothesis that the proportion of those treated with fentanyl alone that have at least a 2-point reduction in their pain will be lower than the proportion of those treated with the combination of fentanyl and single-dose ketamine who have a 2-point reduction in their pain, we will use a chi-square test (or the Fisher's Exact Test if appropriate). An intent to treat approach will be used. We expect the response rate in the two groups to be 40% and 60%, respectively. These estimates are based on the response rates in a study comparing pain management efficacy between subjects treated with morphine alone and morphine plus ketamine.6 With this magnitude of effect, a sample size of 97 per group will have 80% power to detect the difference between the two groups when the critical level of significance is set to 5%. To allow for subject drop-out, protocol deviations, and missing outcome data, we plan to enroll an additional 15% in each arm, for a total of 224 subjects.

Conditions

Acute Traumatic Pain

Outcome Measures

Primary Outcomes (1)

• Reduction in Pain

  reduction in reported pain of two or more points based on the Verbal Numerical Rating Scale.

  between pre-treatment EMS assessment (baseline) and at 30-minutes post-treatment

Study Arms (2)

Ketamine

ACTIVE COMPARATOR

50mg IN Ketamine Hydrochloride

Drug: Ketamine Hydrochloride

Placebo

PLACEBO COMPARATOR

50mg IN placebo

Drug: Placebo-Comparator

Interventions

Ketamine Hydrochloride DRUG

50mg IN Ketamine Hydrochloride

Ketamine

Placebo-Comparator DRUG

50mg IN Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Subjects must be experiencing pain due to acute trauma (i.e. extremity deformity, tourniquet placement, or severe burns).
• A Verbal Numerical Rating Scale pain score ≥7 prior to any pain medication administration.
• Age: ≥18 through 65 years (i.e. subjects must have had their 18th birthday, but not had their 66th birthday).
• Systolic blood pressure ≥100mmHg and \<180mmHg.
• Transported directly from the scene of injury to the Emergency Department at University of Cincinnati Medical Center by a participating EMS agency.
• English-speaking.
• Male sex.
• Subject reported allergy to morphine, fentanyl, or ketamine.
• EMS treatment with ketamine (any), morphine (any), or more than one dose of fentanyl prior to enrollment.
• Inter-facility transfers.
• Prisoners or those in police custody.
• Female sex.
• Paramedic clinical concern of acute agitation or psychosis.
• Pain medication not needed in judgment of prehospital provider.
• Altered level of consciousness, mental status change, or suspected head injury.

Sponsors & Collaborators

• Jason McMullan: lead

Study Sites (1)

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

Location

Related Publications (4)

• McMullan J, Droege C, Strilka R, Hart K, Lindsell C. Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain: Design and Rationale of a Randomized Controlled Trial. Prehosp Emerg Care. 2021 Jul-Aug;25(4):519-529. doi: 10.1080/10903127.2020.1808746. Epub 2020 Oct 15.

  PMID: 32772873 BACKGROUND

• McMullan J, Droege C, Strilka CR, Lindsell C, Linke MJ. Food and Drug Administration and Institutional Review Board Approval of a Novel Prehospital Informed Consent Process for Emergency Research. Prehosp Emerg Care. 2021 Jul-Aug;25(4):512-518. doi: 10.1080/10903127.2020.1806969. Epub 2020 Sep 9.

  PMID: 32790539 BACKGROUND

• Bertolini F, Robertson L, Bisson JI, Meader N, Churchill R, Ostuzzi G, Stein DJ, Williams T, Barbui C. Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experiencing acute traumatic stress symptoms. Cochrane Database Syst Rev. 2024 May 20;5(5):CD013613. doi: 10.1002/14651858.CD013613.pub2.

  PMID: 38767196 DERIVED

• Bertolini F, Robertson L, Bisson JI, Meader N, Churchill R, Ostuzzi G, Stein DJ, Williams T, Barbui C. Early pharmacological interventions for universal prevention of post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2022 Feb 10;2(2):CD013443. doi: 10.1002/14651858.CD013443.pub2.

  PMID: 35141873 DERIVED

MeSH Terms

Interventions

Ketamine

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Fellowship in EMS Medicine; Director-Research, Division of EMS; Associate Professor of Emergency Medicine

Study Record Dates

• First Submitted: August 5, 2016
• First Posted: August 15, 2016
• Study Start: October 3, 2017
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2022
• Last Updated: December 16, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)