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    Clinical Trial Results:
    The analgesic effect of local anaesthetic only compared to local anaesthetic with adjunct of short acting opioid and adrenaline in a continuous paravertebral block for analgesia after VATS – a prospective randomised study.

    Summary
    EudraCT number
    		 2015-002169-50
    Trial protocol
    		 SE  
    Global end of trial date
    14 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Parav20150511
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Solna, Sweden, 17177
    Public contact
    Mark Larsson, Department of Thoracic Surgery, Karolinska, 46 (0)8517 70 914, mark.larsson@karolinska.se
    Scientific contact
    Mark Larsson, Department of Thoracic Surgery, Karolinska, 46 (0)8517 70 914, mark.larsson@karolinska.se
    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
    03 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that the addition of sufentanil and epinephrine to levobupivacaine in continuous paravertebral block will increase its analgesic potency, resulting in better pain relief and enhanced recovery after Video-Assisted Thoracoscopic Surgery despite the lower total levobupivacaine dose administered.
    Protection of trial subjects
    Except for the allocated treatment and the use of a patient-controlled analgesia (PCA) pump, all study participants received care according to standard departmental practice. Investigator ML obtained written informed consent from each patient who agreed to participate in the study after having received oral and written information about the study. All participants were monitored for any adverse events. The trial was approved by the Ethical Review Agency (registration no. 2015/1389-31).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2017
    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
    Sweden: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    16
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients scheduled for lung resection by VATS at the Karolinska University Hospital were considered for enrolment. From 23 October 2017 to 27 April 2020, 76 patients scheduled for VATS were asked to participate. Sixteen patients were ineligible, and the remaining 60 patients were enrolled. After enrolment, 4 were excluded - total = 56 patients.

    Pre-assignment
    Screening details
    		 Patients aged >20 years, with an American Society of Anesthesiologists (ASA) physical status classification of II or III, and the ability to give informed consent were eligible for participation. Reasons for ineligibility were allergy to LAs, pronounced hepatic disease, psychiatric disease or use of psychoactive medication, cognitive impairment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 levobupivacaine-sufentanil-adrenaline (LBSA)
    Arm description
    		 Trial participants were given a continous infusion of levobupivacaine, sufentanil and adrenaline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    levobupivacaine
    Investigational medicinal product code
    Other name
    Chirocaine
    Pharmaceutical forms
    Infusion
    Routes of administration
    Extrapleural use
    Dosage and administration details
    Continous infusion of 1.25 mg/ml levobupivacaine at a rate of 5 ml/h

    Investigational medicinal product name
    sufentanil
    Investigational medicinal product code
    Other name
    Sufenta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Extrapleural use
    Dosage and administration details
    Continous infusion of 0.5 µg/ml sufentanil at a rate of 5 ml/h

    Investigational medicinal product name
    adrenaline
    Investigational medicinal product code
    Other name
    adrenalin mylan
    Pharmaceutical forms
    Infusion
    Routes of administration
    Extrapleural use
    Dosage and administration details
    Continous infusion of 2 µg/ml adrenaline at a rate of 5 ml/h

    Arm title
    		 Levobupivacaine (LB)
    Arm description
    		 Trial participants were given a continous infusion of levobupivacaine alone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    levobupivacaine
    Investigational medicinal product code
    Other name
    Chirocaine
    Pharmaceutical forms
    Infusion
    Routes of administration
    Extrapleural use
    Dosage and administration details
    Continous infusion of 2.7 mg/ml levobupivacaine at a rate of 5 ml/h

    Number of subjects in period 1 [1]
    		levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Started
    27
    29
    Completed
    25
    27
    Not completed
    2
    2
         Lost to follow-up
    2
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: From 23 October 2017 to 27 April 2020, 76 patients scheduled for VATS were asked to participate. Sixteen patients were ineligible, and the remaining 60 patients were enrolled. After enrolment, 4 were excluded - total = 56 patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    levobupivacaine-sufentanil-adrenaline (LBSA)
    Reporting group description
    		 Trial participants were given a continous infusion of levobupivacaine, sufentanil and adrenaline.

    Reporting group title
    Levobupivacaine (LB)
    Reporting group description
    		 Trial participants were given a continous infusion of levobupivacaine alone

    Reporting group values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB) Total
    Number of subjects
    		 27 29 56
    Age categorical
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (62 to 75) 72 (65 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 12 16 28
        Male
    		 15 13 28
    surgical procedure
    Units: Subjects
        Wedge resection, single
    		 0 3 3
        Wedge resection, multiple
    		 0 1 1
        Segmentectomy
    		 4 4 8
        Lobectomy
    		 23 20 43
        Bilobectomy
    		 0 1 1
    Number of ports
    Units: Subjects
        One
    		 11 16 27
        Two
    		 9 8 17
        Three
    		 7 5 12
    weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 81 (64 to 90) 71 (64 to 84) -
    Height
    Units: centimetre
        median (inter-quartile range (Q1-Q3))
    		 174 (164 to 182) 167 (163 to 175) -

    End points

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    End points reporting groups
    Reporting group title
    levobupivacaine-sufentanil-adrenaline (LBSA)
    Reporting group description
    		 Trial participants were given a continous infusion of levobupivacaine, sufentanil and adrenaline.

    Reporting group title
    Levobupivacaine (LB)
    Reporting group description
    		 Trial participants were given a continous infusion of levobupivacaine alone

    Primary: Cumulative PCA-morphine dose at 48 hours

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    End point title
    		 Cumulative PCA-morphine dose at 48 hours
    End point description
    End point type
    Primary
    End point timeframe
    48 hours after surgery
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    24
    27
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    7 (3 to 13.5)
    6 (2 to 10)
    Statistical analysis title
    		 Difference in cumulative PCA-morphine dose 48h
    Statistical analysis description
    Difference in cumulative PCA-morphine requirement at 48 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.378
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Cumulative PCA-morphine dose at 72 hours

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    End point title
    		 Cumulative PCA-morphine dose at 72 hours
    End point description
    End point type
    Primary
    End point timeframe
    72 hours after surgery
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    14
    12
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    12.5 (4 to 21)
    10 (3 to 21.9)
    Statistical analysis title
    		 Difference in cumulative PCA-morphine dose 72h
    Statistical analysis description
    Difference in cumulative PCA-morphine requirement at 72 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.738
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cumulative Pain score at rest - 48 hours

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    End point title
    		 Cumulative Pain score at rest - 48 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) at rest, cumulative over 48 hours
    End point type
    Secondary
    End point timeframe
    cumulative over 48 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    20
    23
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    5.5 (1.5 to 10)
    4 (3 to 6)
    Statistical analysis title
    		 Difference in pain score at rest 48h
    Statistical analysis description
    Difference in pain score at rest, cumulative over 48 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.616
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cumulative Pain score at rest - 72 hours

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    End point title
    		 Cumulative Pain score at rest - 72 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) at rest, cumulative over 72 hours
    End point type
    Secondary
    End point timeframe
    cumulative over 72 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    11
    11
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    9 (4 to 15)
    6 (3 to 12)
    Statistical analysis title
    		 Difference in pain score at rest 72h
    Statistical analysis description
    Difference in pain score at rest, cumulative over 72 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Pain score deep breaths - 24 hours

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    End point title
    		 Pain score deep breaths - 24 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) after two deep breaths, at 24 hours
    End point type
    Secondary
    End point timeframe
    after two deep breaths, at 24 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    26
    28
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    3 (2 to 5)
    2.5 (1 to 3)
    Statistical analysis title
    		 Difference in pain score - deep breaths - 24h
    Statistical analysis description
    Difference in pain score after two deep breaths, at 24 hours
    Comparison groups
    Levobupivacaine (LB) v levobupivacaine-sufentanil-adrenaline (LBSA)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Pain score deep breaths - 30 hours

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    End point title
    		 Pain score deep breaths - 30 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) after two deep breaths, at 30 hours
    End point type
    Secondary
    End point timeframe
    after two deep breaths, at 30 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    27
    29
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    1 (0 to 3)
    Statistical analysis title
    		 Difference in pain score - deep breaths - 30h
    Statistical analysis description
    Difference in pain score after two deep breaths, at 30 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cumulative Pain score deep breaths - 48 hours

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    End point title
    		 Cumulative Pain score deep breaths - 48 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) after two deep breaths, cumulative over 48 hours
    End point type
    Secondary
    End point timeframe
    after two deep breaths, cumulative measurement over 48 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    17
    22
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    14 (8 to 20)
    9.5 (6 to 15)
    Statistical analysis title
    		 Difference in pain score - deep breaths - 48h
    Statistical analysis description
    Difference in pain score after two deep breaths, cumulative over 48 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cumulative Pain score deep breaths - 72 hours

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    End point title
    		 Cumulative Pain score deep breaths - 72 hours
    End point description
    Pain score, indicated by numerical rating scale (NRS) after two deep breaths, cumulative over 72 hours
    End point type
    Secondary
    End point timeframe
    after two deep breaths, cumulative over 72 hours
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    9
    11
    Units: NRS score
        median (inter-quartile range (Q1-Q3))
    20 (17 to 23)
    12 (6 to 23)
    Statistical analysis title
    		 Difference in pain score - deep breaths - 72h
    Statistical analysis description
    Difference in pain score after two deep breaths, cumulative over 72 hours
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.208
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of recovery - POD1

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    End point title
    		 Quality of recovery - POD1
    End point description
    Quality of recovery according to quality of recovery(QoR)-15 questionnaire - POD1 (day 1 after surgery)
    End point type
    Secondary
    End point timeframe
    Day 1 after surgery
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    27
    29
    Units: QoR-15 score
        median (inter-quartile range (Q1-Q3))
    117 (99 to 126)
    118 (106 to 126)
    Statistical analysis title
    		 Difference in QoR-15 score POD1
    Statistical analysis description
    Difference in QoR-15 score 1 day after surgery
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.491
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of recovery - POD21

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    End point title
    		 Quality of recovery - POD21
    End point description
    Quality of recovery according to quality of recovery(QoR)-15 questionnaire - POD21 (day 21 after surgery)
    End point type
    Secondary
    End point timeframe
    21 days after surgery
    End point values
    		 levobupivacaine-sufentanil-adrenaline (LBSA) Levobupivacaine (LB)
    Number of subjects analysed
    25
    27
    Units: QoR-15 Score
        median (inter-quartile range (Q1-Q3))
    124 (109 to 135)
    131 (112 to 143)
    Statistical analysis title
    		 Difference in QoR-15 score POD21
    Statistical analysis description
    Difference in QoR-15 score 21 days after surgery
    Comparison groups
    levobupivacaine-sufentanil-adrenaline (LBSA) v Levobupivacaine (LB)
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.107
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    In-hospital from the start of the intervention to discharge at 48- or 72 hours as well as out-of-hospital up to 21 days after the intervention.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Free text
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    All study subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All study subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 56 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All study subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 56 (42.86%)
    Surgical and medical procedures
    chest tube remained in place after POD1
         subjects affected / exposed
    10 / 56 (17.86%)
         occurrences all number
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 56 (3.57%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    1 / 56 (1.79%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 56 (19.64%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 56 (1.79%)
         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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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