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    Clinical Trial Results:
    PreMeFen

    Summary
    EudraCT number
    		 2021-000549-42
    Trial protocol
    		 NO  
    Global end of trial date
    22 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jun 2026
    First version publication date
    05 Jun 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PreMeFen
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05137184
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oslo University Hospital
    Sponsor organisation address
    Kirkeveien 166, Oslo, Norway, 0450
    Public contact
    Air Ambulance Department, Oslo University Hospital, frihey@ous-hf.no
    Scientific contact
    Air Ambulance Department, Oslo University Hospital, +47 91502770, frihey@ous-hf.no
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Mar 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective 1a To determine if a regimen of inhalation of 3 ml methoxyflurane is non-inferior to a regimen of intranasal 50 µ (>70) or 100 ug (>18, <70 years) fentanyl in reduction of moderate to severe pain (NRS ≥ 4) after 10 min in patients >18 years of age. (Repeated dosing allowed) Primary objective 1b: To determine if a regimen of inhalation of 3 ml methoxyflurane is non-inferior to a regimen of morphine IV 0.1 mg/kg (0.05 mg/kg from >70 years or fragile patients) in reduction of moderate to severe pain (NRS ≥ 4) after 10 min, in patients >18 years of age. (Repeated dosing allowed) Primary objective 1c: To determine if a regimen of intranasal 50 µ(>70 years) or 100 ug (>18, <70 years) fentanyl is non-inferior to a regimen of morphine IV 0.1 mg/kg (or 0.05 mg/kg >70 years old or fragile patients) in reduction of moderate to severe pain (NRS ≥ 4) after 10 min, in patients >18 years of age. (Repeated dosing allowed)
    Protection of trial subjects
    Patients with suboptimal effect of study medication was offered rescue medication with other analgesia than the IMP
    Background therapy
    		 NA
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    08 Nov 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 338
    Worldwide total number of subjects
    338
    EEA total number of subjects
    338
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    166
    From 65 to 84 years
    149
    85 years and over
    23

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period was from November 8 2021 to April 22 2023, and the recruitment was performed in the ambulance service at Innlandet Hospital in Norway

    Pre-assignment
    Screening details
    		 Patients aged 18 years or older with medical or traumatic acute moderate to severe pain scoring 4 or higher on the Numeric Rating Scale (NRS), normal physiology and ability to provide informed consent. Exclusion criteria included life-threatening or limb-threatening conditions, head injuries with neurological impairment and allergies to IMP.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Although this is an open-label study and the ambulance personnel were not masked to treatment allocation, the statistician was masked to the allocations in the dataset until the statistical analysis plan was signed and the database was locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Morphine IV
    Arm description
    		 Patients receiving IV morphine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine IV
    Investigational medicinal product code
    N02AA01
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients 18-69 years received 0.1 mg/kg intravenous morphine (Abcur, Helsingborg, Sweden). Patients 70 years or older received 0.05 mg/kg intravenous morphine. Doses were repeated if needed, with interval of 5 minutes, and maximum doses were 0.5 mg/kg morphine

    Arm title
    		 Fentanyl IN
    Arm description
    		 Patients receiving intranasal Fentanyl
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl IN
    Investigational medicinal product code
    N02AB03
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Patients aged 18–69 years received 100 μg intranasal fentanyl (Takeda Pharma, Vallenback Strans, Denmark) Patients 70 years or older received 50 μg intranasal fentanyl Doses were repeated if needed, with interval of 5 minutes, maximum dose was 500 μg intranasal fentanyl.

    Arm title
    		 Methoxyflurane inhalation
    Arm description
    		 Patients receiving methoxyflurane inhalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methoxyflurane
    Investigational medicinal product code
    N02BG09
    Other name
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received 3 mL inhalational methoxyflurane (Medical Developments NED, Amsterdam, Netherlands) The dose could be repeated, with maximum 6 ml in total.

    Number of subjects in period 1
    		Morphine IV Fentanyl IN Methoxyflurane inhalation
    Started
    111
    115
    112
    Completed
    109
    112
    111
    Not completed
    2
    3
    1
         Physician decision
    2
    -
    -
         Consent withdrawn by subject
    -
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Morphine IV
    Reporting group description
    		 Patients receiving IV morphine

    Reporting group title
    Fentanyl IN
    Reporting group description
    		 Patients receiving intranasal Fentanyl

    Reporting group title
    Methoxyflurane inhalation
    Reporting group description
    		 Patients receiving methoxyflurane inhalation

    Reporting group values
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation Total
    Number of subjects
    		 111 115 112 338
    Age categorical
    Age groups
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 51 61 64 176
        From 65-84 years
    		 52 48 39 139
        85 years and over
    		 8 6 9 23
        18-69
    		 0 0 0 0
        70 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 60 57 58 175
        Male
    		 51 58 54 163

    End points

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    End points reporting groups
    Reporting group title
    Morphine IV
    Reporting group description
    		 Patients receiving IV morphine

    Reporting group title
    Fentanyl IN
    Reporting group description
    		 Patients receiving intranasal Fentanyl

    Reporting group title
    Methoxyflurane inhalation
    Reporting group description
    		 Patients receiving methoxyflurane inhalation

    Primary: Change in pain numeric rating scale at 10 minutes

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    End point title
    		 Change in pain numeric rating scale at 10 minutes
    End point description
    The primary endpoint was change in pain NRS score from baseline to 10 min after treatment start
    End point type
    Primary
    End point timeframe
    From start administration of study drug, to 10 minutes after start of administration
    End point values
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation
    Number of subjects analysed
    90
    89
    102
    Units: Numeric Rating Scale (NRS)
        arithmetic mean (standard deviation)
    -2.74 ( 2.12 )
    -1.98 ( 2.28 )
    -3.31 ( 2.67 )
    Statistical analysis title
    		 Linear model methoxyflurane vs IN fentanyl
    Statistical analysis description
    Linear model comparison of change in NRS for methoxyflurane versus IN fentanyl
    Comparison groups
    Methoxyflurane inhalation v Fentanyl IN
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.01
         upper limit
    		 -0.64
    Statistical analysis title
    		 Linear model methoxyflurane vs IV morphine
    Statistical analysis description
    Linear model comparison of change in NRS for methoxyflurane versus IV morphine
    Comparison groups
    Morphine IV v Methoxyflurane inhalation
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.31
    Statistical analysis title
    		 Linear model IN fentanyl vs IV morphine
    Statistical analysis description
    Linear model comparison of change in NRS for IN fentanyl versus IV morphine
    Comparison groups
    Morphine IV v Fentanyl IN
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.55

    Secondary: Change in pain numeric rating scale at 5 minutes

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    End point title
    		 Change in pain numeric rating scale at 5 minutes
    End point description
    This secondary endpoint was change in pain NRS score from baseline to 5 minutes after treatment start
    End point type
    Secondary
    End point timeframe
    From start administration of study drug, to 5 minutes after start of administration
    End point values
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation
    Number of subjects analysed
    90
    89
    102
    Units: Numeric Rating Scale (NRS)
        arithmetic mean (standard deviation)
    -2.17 ( 1.88 )
    -1.08 ( 1.62 )
    -2.79 ( 2.60 )
    Statistical analysis title
    		 Linear model methoxyflurane vs IN fentanyl
    Statistical analysis description
    Linear model comparison of change in NRS for methoxyflurane versus IN fentanyl
    Comparison groups
    Methoxyflurane inhalation v Fentanyl IN
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 -1.1
    Statistical analysis title
    		 Linear model methoxyflurane vs IV morphine
    Statistical analysis description
    Linear model comparison of change in NRS for methoxyflurane versus IV morphine
    Comparison groups
    Methoxyflurane inhalation v Morphine IV
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 0.18
    Statistical analysis title
    		 Linear model IN fentanyl vs IV morphine
    Statistical analysis description
    Linear model comparison of change in NRS for IN fentanyl versus IV morphine
    Comparison groups
    Morphine IV v Fentanyl IN
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.66

    Secondary: Need for rescue medication

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    End point title
    		 Need for rescue medication
    End point description
    Number of patients receiving rescue medication for pain relief in addition to study drug
    End point type
    Secondary
    End point timeframe
    From administration of study drug to end of study
    End point values
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation
    Number of subjects analysed
    90
    89
    102
    Units: Patients
    14
    26
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start administration of study drug, to end of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.E
    Reporting groups
    Reporting group title
    Morphine IV
    Reporting group description
    		 Patients receiving IV morphine

    Reporting group title
    Fentanyl IN
    Reporting group description
    		 Patients receiving intranasal Fentanyl

    Reporting group title
    Methoxyflurane inhalation
    Reporting group description
    		 Patients receiving methoxyflurane inhalation

    Serious adverse events
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Sedation
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Morphine IV Fentanyl IN Methoxyflurane inhalation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 111 (23.42%)
    27 / 115 (23.48%)
    24 / 112 (21.43%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 115 (0.87%)
    1 / 112 (0.89%)
         occurrences all number
    2
    1
    1
    Hypotension
         subjects affected / exposed
    4 / 111 (3.60%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences all number
    4
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 115 (2.61%)
    3 / 112 (2.68%)
         occurrences all number
    0
    3
    3
    Headache
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 115 (1.74%)
    0 / 112 (0.00%)
         occurrences all number
    0
    2
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    2 / 112 (1.79%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    7 / 111 (6.31%)
    3 / 115 (2.61%)
    5 / 112 (4.46%)
         occurrences all number
    7
    3
    5
    Sedation
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    2 / 112 (1.79%)
         occurrences all number
    0
    0
    2
    Somnolence
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 115 (0.00%)
    1 / 112 (0.89%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    14 / 111 (12.61%)
    11 / 115 (9.57%)
    11 / 112 (9.82%)
         occurrences all number
    14
    11
    11
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    3 / 111 (2.70%)
    5 / 115 (4.35%)
    4 / 112 (3.57%)
         occurrences all number
    3
    5
    4
    Skin and subcutaneous tissue disorders
    Nasal pruritus
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 115 (1.74%)
    0 / 112 (0.00%)
         occurrences all number
    0
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 115 (0.87%)
    0 / 112 (0.00%)
         occurrences all number
    1
    1
    0
    Rash
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 115 (0.00%)
    0 / 112 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/41275876
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