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    Clinical Trial Results:
    Perioperative Methadone for ameliorating postoperative pain and reduction in postoperative opioid consumption in hip fracture patients – Dosage adjusting pilot-study

    Summary
    EudraCT number
    		 2022-001857-22
    Trial protocol
    		 DK  
    Global end of trial date
    04 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2024
    First version publication date
    24 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Methadone-010922
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05581901
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hospital Sønderjylland
    Sponsor organisation address
    Kresten Philipsensvej 15, Aabenraa, Denmark, 6200
    Public contact
    Jesper Ougaard Schønnemann , Department of Orthopaedics, +45 79976170, Jesper.Ougaard.Schoennemann1@rsyd.dk
    Scientific contact
    Jesper Ougaard Schønnemann , Department of Orthopaedics, +45 79976170, Jesper.Ougaard.Schoennemann1@rsyd.dk
    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
    18 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to investigate whether doses greater than 0.10 mg/kg are tolerated with no increased risk of respiratory depression, side-effects, or prolonged stay in the post anesthesia care unit (PACU). This is to ensure that the doses used in the literature are tolerated by the elderly and fragile.
    Protection of trial subjects
    To minimize any risk regarding Methadone administration a specialist in anesthesiology will be present at administration and will supervise subsequent observation. Medical equipment for emergencies are readily available.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    1
    From 65 to 84 years
    17
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients will be screened for inclusion in the emergency department by the orthopedic resident on duty. The patient and next of kin will receive verbal as well as written information about the study, and should be made aware of the study within the first four hours after arrival. They receive two hours to consider. Consent is written and voluntary.

    Pre-assignment
    Screening details
    		 Every patient presenting with an acute hip fracture in the period of the study will be screened for inclusion by the Orthopedic resident. This will ensure sufficient knowledge regarding 'Good Clinical Practice' and the treatment of hip fractures.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Treatment allocation follows the continual reassessment method. The investigator utilizes an adaptive algorithm to assign three patients at a time to one of three dose-groups. An un-blinded nurse prepare the study drug. Carer and subject remain unaware of treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.10 mg/kg
    Arm description
    		 Patients in this group has been allocated to receive 0.10 mg/kg of methadone.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methadone Streuli
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The purchased ampoules contain a sterile solution ready for injection. Study medicine is withdrawn by primary caregiver from the emergency department and is administered by the treating certified nurse anesthetist. The Methadone is administered intravenously at the beginning of the hip fracture surgery (10 minutes before knife-to-skin). The medicine is only administered this one time.

    Arm title
    		 0.15 mg/kg
    Arm description
    		 These patients were allocated to receive 0.15 mg/kg methadone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methadone Streuli
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The purchased ampoules contain a sterile solution ready for injection. Study medicine is withdrawn by primary caregiver from the emergency department and is administered by the treating certified nurse anesthetist. The Methadone is administered intravenously at the beginning of the hip fracture surgery (10 minutes before knife-to-skin). The medicine is only administered this one time.

    Arm title
    		 0.20 mg/kg
    Arm description
    		 These patients were allocated to receive 0.20 mg/kg methadone perioperatively.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methadone Streuli
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The purchased ampoules contain a sterile solution ready for injection. Study medicine is withdrawn by primary caregiver from the emergency department and is administered by the treating certified nurse anesthetist. The Methadone is administered intravenously at the beginning of the hip fracture surgery (10 minutes before knife-to-skin). The medicine is only administered this one time.

    Number of subjects in period 1
    		0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Started
    9
    22
    1
    Completed
    9
    21
    0
    Not completed
    0
    1
    1
         Physician decision
    -
    1
    -
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 32 32
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 17 17
        85 years and over
    		 14 14
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 12 12
    Hip fracture type
    The type of hip fracture
    Units: Subjects
        Collum femoris fracture
    		 22 22
        Pertrochanteric fracture
    		 9 9
        Subtrochanteric fracture
    		 1 1
    ASA classification
    American Society of Anesthesiologists Classification
    Units: Subjects
        ASA 1
    		 0 0
        ASA 2
    		 13 13
        ASA 3
    		 18 18
        ASA 4
    		 1 1
        ASA 5
    		 0 0
        ASA 6
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Included patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All included patients who have completed the trial

    Subject analysis sets values
    		 Included patients
    Number of subjects
    30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    1
        From 65-84 years
    16
        85 years and over
    13
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Hip fracture type
    The type of hip fracture
    Units: Subjects
        Collum femoris fracture
    21
        Pertrochanteric fracture
    8
        Subtrochanteric fracture
    1
    ASA classification
    American Society of Anesthesiologists Classification
    Units: Subjects
        ASA 1
    0
        ASA 2
    13
        ASA 3
    16
        ASA 4
    1
        ASA 5
    0
        ASA 6
    0

    End points

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    End points reporting groups
    Reporting group title
    0.10 mg/kg
    Reporting group description
    		 Patients in this group has been allocated to receive 0.10 mg/kg of methadone.

    Reporting group title
    0.15 mg/kg
    Reporting group description
    		 These patients were allocated to receive 0.15 mg/kg methadone

    Reporting group title
    0.20 mg/kg
    Reporting group description
    		 These patients were allocated to receive 0.20 mg/kg methadone perioperatively.

    Subject analysis set title
    Included patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All included patients who have completed the trial

    Primary: Dose Limiting Toxicity (DLT)

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    End point title
    		 Dose Limiting Toxicity (DLT)
    End point description
    The primary outcome was respiratory depression, which is a binary parameter defined as a respiratory frequency of <10/min and a peripheral oxygen saturation of <94 % despite 4 liters of oxygen/min. The data source was both the observation chart filled in by the primary caregiver at PACU and observation charts filled in at the ward. The nurse at PACU continuously monitored peripheral oxygen saturation and respiratory frequency until the patient could be discharged to the ward. At the orthopedic ward respiratory depression was registered upon arrival and after 6, 24 and 72 hours after surgery by nurses at the ward.
    End point type
    Primary
    End point timeframe
    72 hours post surgery
    End point values
    		 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Number of subjects analysed
    9
    21
    0 [1]
    Units: Respiratory depression
        DLT
    0
    3
        no DLT
    9
    18
    Notes
    [1] - No patients in this group included in statistical analysis
    Statistical analysis title
    		 Continual Reassessment Method
    Statistical analysis description
    This trial uses the Bayesian continual reassessment method.
    Comparison groups
    0.10 mg/kg v 0.15 mg/kg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 The mean posterior estimate of toxicity
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.17
    Variability estimate
    Standard deviation
    Dispersion value
    0.04

    Secondary: Length of stay at the Post Anesthesia Care Unit (PACU)

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    End point title
    		 Length of stay at the Post Anesthesia Care Unit (PACU)
    End point description
    We registered the length of stay at the PACU as hours for each patient. The data source was the observation chart filled in by the primary caregiver at PACU. Discharge from PACU conformed to the national guidelines from the Danish Society for Anesthesiology and Intensive Medicine (DASAIM). Thus, patients had to either meet criteria regarding peripheral oxygen saturation, arousal, and pain level or go through an assessment by an anesthesiologist before discharge.
    End point type
    Secondary
    End point timeframe
    0-12 hours
    End point values
    		 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Number of subjects analysed
    9
    21
    0 [2]
    Units: Hours
        number (not applicable)
    2.8
    2.5
    Notes
    [2] - No patient included in the statistical analysis in this group
    Statistical analysis title
    		 Linear regression
    Statistical analysis description
    we conducted linear regression analysis. We applied bootstrapped confidence intervals in our linear regression model.
    Comparison groups
    0.10 mg/kg v 0.15 mg/kg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.62 [3]
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [3] - (CI -1.48; 0.89)

    Secondary: Amount of antidote needed

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    End point title
    		 Amount of antidote needed
    End point description
    The number of times administration of antidote (Naloxone) was necessary. The limited number of observations precluded the possibility of conducting meaningful statistical analysis. Only one patient received antidote accounting for two out of the 120 possible observations.
    End point type
    Secondary
    End point timeframe
    72 hours post surgery
    End point values
    		 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Number of subjects analysed
    9
    21
    0 [4]
    Units: Binary
    1
    0
    Notes
    [4] - No patient in this group included in statistical analysis
    No statistical analyses for this end point

    Secondary: Opioid consumption

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    End point title
    		 Opioid consumption
    End point description
    We registered postoperative opioid consumption as a mean consumption of rescue morphine equivalents in each group upon arrival and within the first 6 hours after surgery, within the first 24 hours after surgery, and within the first 72 hours after surgery. We calculated the morphine equivalent dose for different types of opioids. The data source was the medical chart and nurses filled in the amount on the observation chart.
    End point type
    Secondary
    End point timeframe
    0-72 hours post surgery
    End point values
    		 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Number of subjects analysed
    9
    21
    0 [5]
    Units: milligram(s)
        number (not applicable)
    9.4
    12.6
    Notes
    [5] - No patient included in statistical analysis in this group.
    Statistical analysis title
    		 negative binomial regression
    Statistical analysis description
    We used a negative binomial regression due to the integer-like nature of the administered dosage. We applied clustered standard errors on the patient ID level, as we deemed the variation distribution within subjects non-reproducible. We used the mean consumption of rescue morphine equivalents from each group in our calculations.
    Comparison groups
    0.10 mg/kg v 0.15 mg/kg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.34
    Method
    		 negative binomial regression
    Parameter type
    		 Incidence risk ratio (IRR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2.07
    Variability estimate
    Standard deviation

    Secondary: Post Operative Nausea or Vomiting (PONV)

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    End point title
    		 Post Operative Nausea or Vomiting (PONV)
    End point description
    We registered PONV binomial as present or not at 6 and 24 hours after surgery. The data source was the patient's statement at the time, which we entered on the observation chart.
    End point type
    Secondary
    End point timeframe
    0-24 hours post surgery
    End point values
    		 0.10 mg/kg 0.15 mg/kg 0.20 mg/kg
    Number of subjects analysed
    9
    21
    0 [6]
    Units: Percentage
        number (not applicable)
    9.1
    9.8
    Notes
    [6] - Patient not included in statistical analysis
    Statistical analysis title
    		 Fisher's exact test
    Comparison groups
    0.10 mg/kg v 0.15 mg/kg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Post Operative Pain Assessment

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    End point title
    		 Post Operative Pain Assessment
    End point description
    We asked patients to assess their pain intensity at the hip using the VRS as this is a validated scale for hip fracture patients. The scale provides patients with six choices and they must choose the one that best describes their pain. The choices are: 0 (no pain), 1 (slight pain), 2 (moderate pain), 3 (severe pain), 4 (extreme pain), and 5 (unbearable/worst imaginable pain). We asked them to assess pain intensity upon arrival at the ward and at 6, 24, and 72 hours after surgery. The data source was the patient's statement at the time, which we entered on the observation chart.
    End point type
    Secondary
    End point timeframe
    0-72 hours post surgery
    End point values
    		 Included patients
    Number of subjects analysed
    30
    Units: Verbal Rating Scale
        No pain
    59
        Slight pain
    36
        Moderate pain
    10
        Severe pain
    0
        Extreme pain
    0
        Unbearable/worst imaginable pain
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The first 12 days after study drug administration.
    Adverse event reporting additional description
    Adverse events were continuously monitored through the hospital stay. After discharge every included patient had a 12-day follow-up phone call where they completed a questionnaire with the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    All included patients
    Reporting group description
    		 All of the 31 patients who were exposed to study drug.

    Serious adverse events
    		 All included patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 31 (3.23%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Cardiac arrest
    Additional description: Circulatory collapse following surgery and general anesthesia.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All included patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 31 (3.23%)
    Nervous system disorders
    Somnolence
    Additional description: The patient was observed excessively sleepy and drowsy. Administration of Naloxone had no effect, thus opioid overdose was ruled out. A combination of dehydration and infection was the underlying cause.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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