A Comparison of Three Regimens of Acute Pain Management: Methoxyflurane; Intranasal Fentanyl; Intravenous Morphine (PreMeFen)

A Randomized Controlled, Open-label, Non-inferiority, Three Arm Clinical Study to Assess Inhalation of Low-dose Methoxyflurane, Intranasal Fentanyl, and Intravenous Morphine for Acute Pain in the Pre-hospital Setting

The study rationale is to provide evidence for early, safe and effective pain management in the ambulance service with non-invasive and fast acting analgesics. Low-dose methoxyflurane and intranasal fentanyl are non-invasive medications that are well-suited for use by ambulance personnel under difficult pre-hospital settings. This is a randomized, controlled, open label, three-arm, non-inferiority, phase 3 drug trial performed in the ambulance service. The randomization will be 1:1:1 to the three treatment groups.

Patients 18 years or older with acute pain with Numeric Rating Scale (NRS) ≥4 with normal physiology and capable of giving informed consent will be included null hypothesis (H0) (tested in hierarchic order a-b-c):

1. Methoxyflurane regimen is inferior to intranasal fentanyl regimen or
2. Methoxyflurane regimen is inferior to IV morphine regimen or
3. Intranasal fentanyl regimen is inferior to IV morphine regimen for treating moderate to severe pain, measured by reduction in Numeric Rating Scale (NRS) 10 minutes after administration.

The study duration for each participant will be from ambulance scene arrival to patient handover in emergency department.

Number of participants: Patient enrolment until successful inclusion of 270 per protocol patients.

Primary endpoint is change in NRS from before administration (t0) to 10 minutes after start of administration (t10).

The study intervention is one of the three IMPs:

• Methoxyflurane: 3 ml inhalation, can be repeated once to a total dose of 6 ml.
• Fentanyl intranasal spray: 100 µg IntraNasal, (patients >70 years 50 µg), can be repeated to maximum total dose 500 µg IN.
• Morphine hydrochloride intravenous: 0.1 mg/kg IV (patients >70 years or fragile 0.05 mg/kg IV), can be repeated to a maximum total dose 0.5 mg/kg IV.

Rescue analgesia is all analgesics other than the allocated IMP. If rescue medication is administered before the assessment of primary endpoint at 10 minutes, the patient will not be part of the per-protocol analysis.

The hypothesis will be tested and the primary endpoint will be evaluated by the 95% confidence limits (95% CI), and a conclusion of non-inferiority will be made if the 95% CI of the estimated treatment difference fully lie within the inferiority margin. Non-inferiority is determined on the basis of a 1-sided equivalence t test on the per protocol population and confirmed, for sensitivity reasons, on the modified intention to treat population.

Study Overview

• Status: Completed
• Conditions: Acute Pain; Ambulances
• Intervention / Treatment: Drug: Methoxyflurane; Drug: Fentanyl; Drug: Morphine hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 338
• Phase: Phase 3

Contacts and Locations

Study Locations

• Norway
  • Gjøvik, Norway
    • Sykehuset Innlandet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 18 years of age
2. Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS
3. Capable of giving informed consent
4. Normal physiology

Exclusion Criteria:

1. Life-threatening or limb-threatening condition requiring immediate management
2. Pregnancy or breastfeeding
3. Know allergies, hypersensitivity or serious side effects to opioids or methoxyflurane or other excipients
4. Head injury or medical conditions with neurological impairment (Glasgow Coma Scale (GCS)<14)
5. Previous malignant hyperthermia or persons with suspect genetic predisposition for malignant hyperthermia
6. Massive facial trauma, visible nasal blockage or on-going nose bleeding
7. History of severe liver disease with jaundice and scleral icterus
8. Dialysis or history of severe renal disease (known chronic kidney failure stage 4 or 5)
9. Mono Amine Oxidase-inhibitors last 14 days (pharmacological treatment of depression, Mb Parkinson or narcolepsy)
10. Myasthenia gravis
11. Use of investigational medicinal product (IMP) analgesics 12 hours prior to inclusion
12. Any condition that in the view of the study worker would suggest that the patient is unable to comply with study protocol and procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methoxyflurane; 3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml	Drug: Methoxyflurane; Inhalation of Methoxyflurane
Experimental: Fentanyl IN; 100 µg IntraNasal, Patients >70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN	Drug: Fentanyl; Intranasal Fentanyl
Active Comparator: Morphine IV; 0.1 mg/kg Intravenous (IV) Patients ≥ 70 years or fragile: 0.05 mg/kg IV Can be repeated Maximum total dose 0.5 mg/kg IV	Drug: Morphine hydrochloride; Intravenous Morphine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain Numeric Rating Scale after 10 minutes	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 10 minutes after start of IMP administration	10 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain Numeric Rating Scale after 5 minutes	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 5 minutes after start of IMP administration	5 minutes
Change in pain Numeric Rating Scale after 20 minutes	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 20 minutes after start of IMP administration	20 minutes
Change in pain Numeric Rating Scale after 30 minutes	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 30 minutes after start of IMP administration	30 minutes
Need for rescue analgesia	Number of patients with administration of rescue analgesia	2 hours
Type of rescue analgesia	Type of rescue analgesia administered	2 hours
Dose of rescue analgesia	Dose of rescue analgesia administered	2 hours
Route of administration of rescue analgesia	Route of administration of rescue analgesia	2 hours
Time from ambulance arrival to IMP administration	Time from arrival of ambulance personnel by the patient to administration of IMP	1 hour
Time from ambulance arrival to 2-point NRS reduction	Time from ambulance arrival to first measure of a reduction in NRS of 2 points or more	1 hour
Change in level of sedation	Change in GCS from baseline to 10 and 30 minutes	30 minutes
Change in respiration	Change in respiratory rate from baseline to 10 and 30 minutes	30 minutes
Change in blood pressure	Change in systolic blood pressure from baseline to 10 and 30 minutes	30 minutes
Health Care Personnel Likert Scale	Likert Scale (1 to 5, higher is better) of health care professional satisfaction at end of mission	2 hours
Patient Likert Scale	Likert Scale (1 to 5, higher is better) of patient satisfaction at end of mission	2 hours
Numbers of patients with adverse events in each treatment group	Registration of adverse events during study period until end of intervention and compare numbers of patient with adverse events in each group	2 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain Numeric Rating Scale after 10 minutes stratified by diagnosis groups	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) stratified by diagnosis groups	30 minutes
Need for rescue medication related to painful procedures	Proportion of patient receiving rescue treatment related to procedures (reposition of fractures, relocation etc)	2 hours
Number of vascular cannulation attempts in each patient	Attempts and success of vascular cannulation access in each patient, stratified by treatment allocation	2 hours
Ambulance worker competence influence on change pain Numeric Rating Scale after 10 minutes	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 10 minutes after start of IMP administration stratified by ambulance worker competence (educational levels)	2 hours
Ambulance worker competence influence on patient satisfaction Likert Scale	Likert Scale (1 to 5, higher is better) of patient satisfaction at end of mission, stratified by ambulance worker competence (educational levels)	2 hours
Change in pain Numeric Rating Scale after 10 minutes in acute coronary syndrome patients	Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 10 minutes after start of IMP administration stratified by the presence of acute coronary syndrome defined by troponin elevation higher than 99 percentile or significant ST-segment elevation on any ECG lead.	2 hours

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University of Oslo; Sykehuset Innlandet HF; Norwegian Air Ambulance Foundation
• Investigators: Principal Investigator: Fridtjof Heyerdahl, MD PhD, Senior consultant

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2021
• Primary Completion (Actual): April 22, 2023
• Study Completion (Actual): April 22, 2023

Study Registration Dates

• First Submitted: November 1, 2021
• First Submitted That Met QC Criteria: November 29, 2021
• First Posted (Actual): November 30, 2021

Study Record Updates

• Last Update Posted (Actual): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Morphine; Fentanyl; Methoxyflurane
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Inhalation; Fentanyl; Morphine; Methoxyflurane
• Other Study ID Numbers: 255159; 2021-000549-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No