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

NCT ID: NCT05137184

Last Updated: 2023-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 338 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-12
• Study Completion Date: 2023-04-22

Brief 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.

Conditions

Acute Pain; Ambulances

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Methoxyflurane

3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml

Group Type: EXPERIMENTAL

Methoxyflurane

Intervention Type: DRUG

Inhalation of Methoxyflurane

Fentanyl IN

100 µg IntraNasal, Patients \>70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN

Group Type: EXPERIMENTAL

Fentanyl

Intervention Type: DRUG

Intranasal Fentanyl

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

Group Type: ACTIVE_COMPARATOR

Morphine hydrochloride

Intervention Type: DRUG

Intravenous Morphine

Interventions

Methoxyflurane

Inhalation of Methoxyflurane

Intervention Type: DRUG

Fentanyl

Intranasal Fentanyl

Intervention Type: DRUG

Morphine hydrochloride

Intravenous Morphine

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sykehuset Innlandet HF

OTHER

Sponsor Role: collaborator

Norwegian Air Ambulance Foundation

OTHER

Sponsor Role: collaborator

University of Oslo

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Fridtjof Heyerdahl

Senior Consultant

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fridtjof Heyerdahl, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Senior Consultant

Locations

Sykehuset Innlandet

Gjøvik, , Norway

Countries

Norway

Other Identifiers

2021-000549-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

255159

Identifier Type: -

Identifier Source: org_study_id