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

Study Overview
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Brief Summary
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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): Methoxyflurane regimen is inferior to intranasal fentanyl regimen or Methoxyflurane regimen is inferior to IV morphine regimen or 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.

Official Title
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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

Conditions
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Acute Pain, Ambulances

Intervention / Treatment
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* Drug: Methoxyflurane
* Drug: Fentanyl
* Drug: Morphine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS Capable of giving informed consent Normal physiology Exclusion Criteria: Life-threatening or limb-threatening condition requiring immediate management Pregnancy or breastfeeding Know allergies, hypersensitivity or serious side effects to opioids or methoxyflurane or other excipients Head injury or medical conditions with neurological impairment (Glasgow Coma Scale (GCS)<14) Previous malignant hyperthermia or persons with suspect genetic predisposition for malignant hyperthermia Massive facial trauma, visible nasal blockage or on-going nose bleeding History of severe liver disease with jaundice and scleral icterus Dialysis or history of severe renal disease (known chronic kidney failure stage 4 or 5) Mono Amine Oxidase-inhibitors last 14 days (pharmacological treatment of depression, Mb Parkinson or narcolepsy) Myasthenia gravis Use of investigational medicinal product (IMP) analgesics 12 hours prior to inclusion Any condition that in the view of the study worker would suggest that the patient is unable to comply with study protocol and procedures.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methoxyflurane<br>3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml | Drug: Methoxyflurane<br>* Inhalation of Methoxyflurane<br>|
| Experimental: Fentanyl IN<br>100 µg IntraNasal, Patients >70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN | Drug: Fentanyl<br>* Intranasal Fentanyl<br>|
| Active Comparator: Morphine IV<br>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<br>* Intravenous Morphine<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methoxyflurane, Fentanyl, Morphine