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

Acute Pain Clinical Trial

— PreMeFen  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05137184
• Other study ID #: 255159
• Secondary ID: 2021-000549-42
• Status: Completed
• Phase: Phase 3
• Start date: November 12, 2021
• Est. completion date: April 22, 2023

Study information

• Verified date: November 2023
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 338
• Est. completion date: April 22, 2023
• Est. primary completion date: April 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Pain
• Ambulances

Intervention

Drug:
• Methoxyflurane
Inhalation of Methoxyflurane
• Fentanyl
Intranasal Fentanyl
• Morphine hydrochloride
Intravenous Morphine

Locations

Country	Name	City	State
Norway	Sykehuset Innlandet	Gjøvik

Sponsors (4)

Lead Sponsor	Collaborator
Oslo University Hospital	Norwegian Air Ambulance Foundation, Sykehuset Innlandet HF, University of Oslo

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Need for rescue medication related to painful procedures	Proportion of patient receiving rescue treatment related to procedures (reposition of fractures, relocation etc)	2 hours
Other	Number of vascular cannulation attempts in each patient	Attempts and success of vascular cannulation access in each patient, stratified by treatment allocation	2 hours
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Need for rescue analgesia	Number of patients with administration of rescue analgesia	2 hours
Secondary	Type of rescue analgesia	Type of rescue analgesia administered	2 hours
Secondary	Dose of rescue analgesia	Dose of rescue analgesia administered	2 hours
Secondary	Route of administration of rescue analgesia	Route of administration of rescue analgesia	2 hours
Secondary	Time from ambulance arrival to IMP administration	Time from arrival of ambulance personnel by the patient to administration of IMP	1 hour
Secondary	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
Secondary	Change in level of sedation	Change in GCS from baseline to 10 and 30 minutes	30 minutes
Secondary	Change in respiration	Change in respiratory rate from baseline to 10 and 30 minutes	30 minutes
Secondary	Change in blood pressure	Change in systolic blood pressure from baseline to 10 and 30 minutes	30 minutes
Secondary	Health Care Personnel Likert Scale	Likert Scale (1 to 5, higher is better) of health care professional satisfaction at end of mission	2 hours
Secondary	Patient Likert Scale	Likert Scale (1 to 5, higher is better) of patient satisfaction at end of mission	2 hours
Secondary	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