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    Clinical Trial Results:
    Intrathecal morphine for minimally invasive direct coronary artery bypass surgery: a multicentre, double blind, prospective randomized placebo-controlled trial

    Summary
    EudraCT number
    		 2022-003684-14
    Trial protocol
    		 BE  
    Global end of trial date
    23 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DH11/2022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Anesthesiology, University Hospitals Leuven, +32 16344270, danny.hoogma@uzleuven.be
    Scientific contact
    Anesthesiology, University Hospitals Leuven, +32 16344270, danny.hoogma@uzleuven.be
    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
    15 Apr 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The goal of our study is to improve perioperative care with the use of a multimodal opioid sparing strategy after minimally invasive cardiac surgery for coronary bypass.
    Protection of trial subjects
    Rescue analgesia will be provided according to a standardized protocol. Following extubation, the severity of pain will be assessed at rest and during coughing using an 11-point numeric rating scale (NRS) for pain. NRS 0 = no pain, 1-3 = presence of pain but no additional treatment necessary. In case of NRS > 4, a clinical bolus (1-2 mg) of morphine will be given to the patient. This can be repeated, if however, NRS is >5 during two consecutive assessments, morphine 0.1 mg/kg SC (minimum interval of 4 hours) will be administered. If the pain is localized to the drains insertion site and does not respond to morphine, an additional infiltration of 10 mL of ropivacaine 0.5 % can be considered or if deemed possible, the drain will be removed. Moreover, morphine is not sufficient to treat ‘pericarditis pain’. The latter is expressed as sharp, stabbing chest pain and is mainly diagnosed based on clinical suspicion AND the documentation of new widespread ST-segment elevations or PR depression on the electrocardiogram.15 These patients will be treated with acetylsalicylic acid 500 mg IV every 8 hours and colchicine 1 mg orally twice a day.15 Finally, if pain treatment is still considered insufficient (NRS for pain >6), ibuprofen IV 10 mg/kg (max 600 mg) will be administered or a bolus of ketamine IV 0.1 mg/kg will be given
    Background therapy
    		 Multimodal analgesic treatment as per protocol in our ERACS program
    Evidence for comparator
    		 The comparator is the standard of care.
    Actual start date of recruitment
    01 May 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
    Belgium: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    36
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 113 patients between May 21th 2023 and July 18th 2024 were screened of whom 72 were eligible for participation.

    Pre-assignment
    Screening details
    		 All consecutive adult patients scheduled for either RAMIDCAB surgery were evaluated for enrollment according to the inclusion criteria. They were included if 18-75 years of age, BMI <35, EuroSCORE <3, and admitted to the postoperative ERAS program at the PACU or ICU.

    Period 1
    Period 1 title
    Pre-surgery (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    To avoid bias, treatment arms will be blinded to investigators, medical staff, nurses and participants as follows: The IMP will be manufactured, packaged and labelled in such a way that the visual appearance, nor the smell and/or touch of the IMP can be distinguished from the comparator treatment and/or placebo. Furthermore, to maintain the blind, the IMP and any comparator treatment(s) and/or placebo will follow the same administration route and process.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention group
    Arm description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being 5 µg/kg morphine 0.1% (with a maximum of 500 µg), and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1ml/kg, being normal saline 0.9%.
    Arm type
    		 Experimental

    Investigational medicinal product name
    morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    This group will receive sequentially intrathecal 5 µl/kg of trial medication, being 5 µg/kg morphine 0.1% (with a maximum of 500 µg), and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1ml/kg, being normal saline 0.9%.

    Arm title
    		 Control
    Arm description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being normal saline, and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1 ml/kg, being morphine 0.1%.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intratracheal use
    Dosage and administration details
    This group will receive sequentially intrathecal 5 µl/kg of trial medication, being normal saline, and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1 ml/kg, being morphine 0.1%.

    Number of subjects in period 1
    		Intervention group Control
    Started
    36
    36
    Included
    36
    36
    Completed
    35
    36
    Not completed
    1
    0
         Failed spinal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention group
    Reporting group description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being 5 µg/kg morphine 0.1% (with a maximum of 500 µg), and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1ml/kg, being normal saline 0.9%.

    Reporting group title
    Control
    Reporting group description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being normal saline, and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1 ml/kg, being morphine 0.1%.

    Reporting group values
    		 Intervention group Control Total
    Number of subjects
    		 36 36 72
    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
        geometric mean (standard deviation)
    		 64.3 ( 7.6 ) 64.9 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 32 35 67

    End points

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    End points reporting groups
    Reporting group title
    Intervention group
    Reporting group description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being 5 µg/kg morphine 0.1% (with a maximum of 500 µg), and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1ml/kg, being normal saline 0.9%.

    Reporting group title
    Control
    Reporting group description
    		 This group will receive sequentially intrathecal 5 µl/kg of trial medication, being normal saline, and 0.125 mg/kg hyperbaric bupivacaine 0.5%. At the end of surgery, the patient will receive an intravenous bolus of trial medication 0.1 ml/kg, being morphine 0.1%.

    Primary: Quality of recovery 40

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    End point title
    		 Quality of recovery 40
    End point description
    The primary outcome variable of this investigation will be the postoperative QoR-40 score taken approximately 24 hours postoperatively. This questionnaire consist of 40 items rated by the patient as valid or non-valid on a scale of 5 with a score range between 40-200. Assuming a SD QoR-40 score of 9 points in both groups and assuming no relevant differences between both study centres, 34 patients per group are required to have at least 80% power to show a minimal clinically important difference of 6.3 points between the intervention group and control group based on a two-sided two sample t-test with alpha=0.05.
    End point type
    Primary
    End point timeframe
    24 hours postoperatively
    End point values
    		 Intervention group Control
    Number of subjects analysed
    35 [1]
    36
    Units: 40-200
        median (inter-quartile range (Q1-Q3))
    185.0 (175 to 193)
    180.5 (170.5 to 189.5)
    Notes
    [1] - 1 failed spinal
    Statistical analysis title
    		 SAP
    Statistical analysis description
    A parametric regression model with the treatment group and the study centre as covariates was used.
    Comparison groups
    Intervention group v Control
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 10.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 hours postoperatively
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28
    Reporting groups
    Reporting group title
    Adverse event postop
    Reporting group description
    		 -

    Serious adverse events
    		 Adverse event postop
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 71 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adverse event postop
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 71 (8.45%)
    Skin and subcutaneous tissue disorders
    Pruritis
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    6

    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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