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    Clinical Trial Results:
    Pharmacodynamics of Liposomal Bupivacaine for Peripheral Nerve Blockade: A Randomized, Triple-blinded, Cross Over Study in Volunteers

    Summary
    EudraCT number
    		 2023-000035-74
    Trial protocol
    		 AT  
    Global end of trial date
    22 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2024
    First version publication date
    01 Jun 2024
    Other versions
    Summary report(s)
    		 Journal Article

    Trial information

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    Trial identification
    Sponsor protocol code
    1.3_19.04.2023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Department of Clinical Pharmcology, Medical University Vienna, klin-pharmakologie@meduniwien.ac.at
    Scientific contact
    Department of Clinical Pharmcology, Medical University Vienna, klin-pharmakologie@meduniwien.ac.at
    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
    22 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: Duration of sensory nerve blockade
    Protection of trial subjects
    Trial subjects were monitored during the whole study. One week after the last visit there was a control phone call.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 2023
    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
    Austria: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 27 subjects (healthy volunteers) have been assessed for eligibility and have been recruited. After finishing the first study day 2 subjects of the 27 declined to participate on the second study day. These 2 subjects were excluded.

    Pre-assignment
    Screening details
    		 Healthy volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) were recruited via the Department of Clinical Pharmacology (Medical University of Vienna). Explanation regarding the purpose and risks associated with the study and written informed consent was performed in accor- dance with the standards of the Department of Clinical

    Period 1
    Period 1 title
    Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    The trail was a triple-blinded cross-over study. Neither the physician who performed the ulnar nerve block, nor the physicians executing the sensory and motor tests nor the study participants knew which drug was administered at which study day. The sequence was determined by the randomization.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Exparel
    Arm description
    		 Each subject received an ulnar nerve block with Exparel (liposomal bupivacaine). Two subjects who were treated with Exparel on the first study day withdraw their consent after this first study day. These two subjects were excluded from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exparel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    The nerve block was performed with 13.3mg Exparel

    Arm title
    		 Bupivacaine
    Arm description
    		 Each subject received an ulnar nerve block with plain bupivacaine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Carbostesin
    Investigational medicinal product code
    Other name
    Bupivacaine
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    Each subject received 15mg bupivacaine

    Number of subjects in period 1
    		Exparel Bupivacaine
    Started
    27
    25
    Study day 1
    27
    25
    Study day 2
    25
    25
    Completed
    25
    25
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exparel
    Reporting group description
    		 Each subject received an ulnar nerve block with Exparel (liposomal bupivacaine). Two subjects who were treated with Exparel on the first study day withdraw their consent after this first study day. These two subjects were excluded from the study.

    Reporting group title
    Bupivacaine
    Reporting group description
    		 Each subject received an ulnar nerve block with plain bupivacaine.

    Reporting group values
    		 Exparel Bupivacaine Total
    Number of subjects
    		 27 25 27
    Age categorical
    all study participants were healthy volunteers aged 18-55 years
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 25 27
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 13 13 13
        Male
    		 14 12 14
    Subject analysis sets

    Subject analysis set title
    Study day 1 and 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    As two subjects declined to participate on study day 2 they were excluded

    Subject analysis sets values
    		 Study day 1 and 2
    Number of subjects
    25
    Age categorical
    all study participants were healthy volunteers aged 18-55 years
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    25
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    13
        Male
    12

    End points

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    End points reporting groups
    Reporting group title
    Exparel
    Reporting group description
    		 Each subject received an ulnar nerve block with Exparel (liposomal bupivacaine). Two subjects who were treated with Exparel on the first study day withdraw their consent after this first study day. These two subjects were excluded from the study.

    Reporting group title
    Bupivacaine
    Reporting group description
    		 Each subject received an ulnar nerve block with plain bupivacaine.

    Subject analysis set title
    Study day 1 and 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    As two subjects declined to participate on study day 2 they were excluded

    Primary: Success of sensory blockade

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    End point title
    		 Success of sensory blockade
    End point description
    End point type
    Primary
    End point timeframe
    whole study period
    End point values
    		 Exparel Bupivacaine
    Number of subjects analysed
    25
    25
    Units: subjects
    8
    25
    Statistical analysis title
    		 Success of sensory blockade
    Statistical analysis description
    The study was designed in a cross over manner - so each subject received two nerve blocks - once with liposomal bupivacaine and once with plain bupivacaine. In this setting each participant was their own control.
    Comparison groups
    Exparel v Bupivacaine
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Wilcoxon and McNemar
    Confidence interval
    Notes
    [1] - Wilcoxon signed-rank tests were used for nonparametric paired samples and exact McNemar’s tests to compare the primary endpoint of the study, namely the success of sensory blockade.
    [2] - two-tailed

    Primary: Duration of sensory blockade

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    End point title
    		 Duration of sensory blockade
    End point description
    End point type
    Primary
    End point timeframe
    Duration of sensory blockade was measured after ulnar nerve block. The study was designed in a cross over manner - each subject received two nerve blocks - once with Exparel and once with bupivacaine.
    End point values
    		 Exparel Bupivacaine
    Number of subjects analysed
    25
    25
    Units: minute
        median (inter-quartile range (Q1-Q3))
    375 (345 to 435)
    562 (450 to 610)
    Statistical analysis title
    		 Duration of sensory blockade
    Comparison groups
    Exparel v Bupivacaine
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05 [4]
    Method
    		 Wilcoxon and McNemar
    Confidence interval
    Notes
    [3] - Wilcoxon signed-rank tests were used for nonparametric paired samples and exact McNemar’s tests to compare the primary endpoint of the study.
    [4] - two-tailed

    Secondary: Onset of sensory blockade

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    End point title
    		 Onset of sensory blockade
    End point description
    End point type
    Secondary
    End point timeframe
    measured after each nerve blockade
    End point values
    		 Exparel Bupivacaine
    Number of subjects analysed
    25
    25
    Units: minute
        median (inter-quartile range (Q1-Q3))
    105 (60 to 150)
    15 (10 to 30)
    No statistical analyses for this end point

    Secondary: Success of motor blockade

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    End point title
    		 Success of motor blockade
    End point description
    End point type
    Secondary
    End point timeframe
    measured after each nerve block
    End point values
    		 Exparel Bupivacaine
    Number of subjects analysed
    25
    25
    Units: subject
    0
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Exparel
    Reporting group description
    		 One study participant reported experiencing muscle pain at the injection site after the administration of Exparel. The pain spontaneously resolved within 24 h after administration of Exparel.

    Reporting group title
    Bupivacaine
    Reporting group description
    		 no adverse events in this reporting group

    Serious adverse events
    		 Exparel Bupivacaine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Exparel Bupivacaine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 25 (0.00%)
    Skin and subcutaneous tissue disorders
    Muscle discomfort
    Additional description: One volunteer (no. 17) reported experiencing muscle pain in the puncture area, which spontaneously resolved within 24 h after administration of liposomal bupivacaine.
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    1
    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.
    Obviously, our study was conducted in volunteers without undergoing surgery. These trials have their drawbacks. Thus, studies comparing sensory testing methods in volunteers with the clinical setting of postoperative analgesia are needed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38558118
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