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    Clinical Trial Results:
    A double-blind, randomised placebo-controlled trial to determine whether low-dose intravenous ketamine peri-operatively can prevent chronic post-surgical pain, in patients undergoing thoracotomy or video assisted thoracic surgery (VATS).

    Summary
    EudraCT number
    		 2011-000506-21
    Trial protocol
    		 GB  
    Global end of trial date
    09 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Sep 2016
    First version publication date
    14 Sep 2016
    Other versions
    Summary report(s)
    		 Final report

    Trial information

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    Trial identification
    Sponsor protocol code
    Chumbley1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College Healthcare NHS Trust
    Sponsor organisation address
    Praed Street, London, United Kingdom, W2 1NY
    Public contact
    Rebecca Ward, Research Governance Manager, Imperial College Healthcare NHS Trust, 0044 2075949459, becky.ward@imperial.ac.uk
    Scientific contact
    Rebecca Ward, Research Governance Manager, Imperial College Healthcare NHS Trust, 0044 2075949459, becky.ward@imperial.ac.uk
    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
    31 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary aim of this research is to question whether a low-dose ketamine infusion given for 96 hours during and after surgery, will reduce the incidence of chronic post-surgical pain, 6 weeks after surgery, in patients undergoing thoracotomy and video assisted thoracic surgery (VATS). The study is primarily two studies, one for patients undergoing thoracotomy and the other for patients undergoing VATS. There were to be 72 patient in the thoracotomy trial and 72 patient in the VATS trial. We were unable to complete the VATS trial due to a lack of subjects. These patients were in the advanced stages of cancer and did not want to participate.
    Protection of trial subjects
    The study was investigating pain. All patients received their normal pain management, but the study group received an extra infusion of ketamine or placebo. If the patients were still experiencing pain at the first follow-up session the GP was contacted and a regimen suggested to treat persistent pain after surgery.
    Background therapy
    		 All patient received their normal pain relief, which was agreed on discussion with the patient and their anaesthetist. This consisted of either an epidural infusion or patient-controlled analgesia, plus or minus a paravertebral infusion for those patients have a thoracotomy. For patients having VATS surgery, they received patient-controlled analgesia, plus or minus a paravertebral infusion.
    Evidence for comparator
    		 The comparator was saline placebo.
    Actual start date of recruitment
    10 Jan 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    45
    From 65 to 84 years
    58
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult patients aged 18 years and over, who were booked for either a thoracotomy or VATS procedure at Imperial College Healthcare NHS Trust were invited to participate in the study. They had to be able to read and speak English in order to answer the detailed pain questionnaires.

    Pre-assignment
    Screening details
    		 Patients were excluded if they refusal to participate, if they had previous chronic thoracic pain, neuropathic pain existing at time of recruitment or were taking the one of the following medications: strong opioids (step 3 analgesics), tricyclic antidepressants, venlaflaxine, gabapentin, pregabalin

    Pre-assignment period milestones
    Number of subjects started
    		 104
    Number of subjects completed

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Patients were blinded to whether they received an infusion of ketamine or a saline placebo, both bags looked and were labelled the same. The infusion bags were made up in the aseptic infusion department in pharmacy. The investigators were blind to the type of infusion that the patients received and the blinding remained unbroken until all of the participants had completed their 12 month follow up.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ketamine
    Arm description
    		 Patients who received ketamine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine
    Investigational medicinal product code
    PL 00057/0530
    Other name
    Ketelar
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 0.1mg/kg/hour intravenous infusion running for 96 hours

    Arm title
    		 Saline Placebo
    Arm description
    		 Patients received a saline placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    O.9% sodium chloride
    Investigational medicinal product code
    Other name
    saline
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infusion run at same rate as ketamine

    Number of subjects in period 1
    		ketamine Saline Placebo
    Started
    52
    52
    6 week follow-up
    47
    52
    12 months follow-up
    36
    38
    Completed
    36
    38
    Not completed
    16
    14
         Patient died of cancer
    7
    7
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    8
    7

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 104 104
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 45 45
        From 65-84 years
    		 58 58
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.84 ( 15.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 43
        Male
    		 61 61
    Pain score on moving
    Pain score on moving, 0 (no pain), 10 (worst pain
    Units: numerical
        arithmetic mean (full range (min-max))
    		 0.5 (0 to 7) -
    Worst pain in previous 24 hours
    Worst pain in previous 24 hours, 0(no pain) to 10 (worst pain)
    Units: numerical
        arithmetic mean (full range (min-max))
    		 0.93 (0 to 8) -
    SLANSS
    Short form of the Leeds Assessment of Neuropathic Signs and Symptoms (0 to 24 score). Score over 12 is considered to be neuropathic pain
    Units: numerical
        arithmetic mean (full range (min-max))
    		 0.7 (0 to 14) -

    End points

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    End points reporting groups
    Reporting group title
    ketamine
    Reporting group description
    		 Patients who received ketamine

    Reporting group title
    Saline Placebo
    Reporting group description
    		 Patients received a saline placebo

    Primary: Pain on moving at 6 weeks

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    End point title
    		 Pain on moving at 6 weeks
    End point description
    Pain scores on moving at 6 weeks
    End point type
    Primary
    End point timeframe
    Pain on moving at 6 weeks
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    47
    52
    Units: numerical
        arithmetic mean (standard deviation)
    2.02 ( 2.27 )
    1.4 ( 2.06 )
    Statistical analysis title
    		 Mann-Whitney U test
    Statistical analysis description
    Mann-Whitney U test to compare the ketamine and placebo groups
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mann-Whitney
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Variability estimate
    Standard deviation

    Primary: Worst pain score at 6 weeks

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    End point title
    		 Worst pain score at 6 weeks
    End point description
    Worst pain score in past 24 hours measured at 6 weeks.
    End point type
    Primary
    End point timeframe
    Worst pain score in past 24 hours measured at 6 weeks.
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    47
    52
    Units: numerial
        arithmetic mean (standard deviation)
    2.82 ( 2.595 )
    2.21 ( 2.531 )
    Statistical analysis title
    		 Mann-Whitney U test
    Statistical analysis description
    Comparing means of worst pain at 6 weeks in ketamine and placebo group
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Variability estimate
    Standard deviation

    Primary: S-Lanns pain score at 6 weeks

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    End point title
    		 S-Lanns pain score at 6 weeks
    End point description
    S-Lanns pain score measured at 6 weeks
    End point type
    Primary
    End point timeframe
    S-Lanns pain score measured at 6 weeks
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    47
    52
    Units: numerical
        arithmetic mean (standard deviation)
    5.83 ( 6.709 )
    4.02 ( 5.949 )
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 24
    Variability estimate
    Standard deviation

    Secondary: Pain on moving at 12 months

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    End point title
    		 Pain on moving at 12 months
    End point description
    Pain score on Moving at 12 months
    End point type
    Secondary
    End point timeframe
    Pain score on moving at 12 months
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    36
    38
    Units: numerical
        arithmetic mean (standard deviation)
    0.39 ( 1.695 )
    0.34 ( 1.047 )
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Variability estimate
    Standard deviation

    Secondary: Worst pain score at 12 months

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    End point title
    		 Worst pain score at 12 months
    End point description
    Worst pain score on moving at 12 months.
    End point type
    Secondary
    End point timeframe
    Worst pain score on moving at 12 months.
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    36
    38
    Units: numerical
        arithmetic mean (standard deviation)
    0.58 ( 1.779 )
    0.53 ( 1.72 )
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Variability estimate
    Standard deviation

    Secondary: S-Lanns pain score at 12 months

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    End point title
    		 S-Lanns pain score at 12 months
    End point description
    S-Lanns pain score at 12 months
    End point type
    Secondary
    End point timeframe
    S-Lanns pain score at 12 months
    End point values
    		 ketamine Saline Placebo
    Number of subjects analysed
    36
    38
    Units: numerical
        arithmetic mean (standard deviation)
    2.17 ( 5.107 )
    1.32 ( 4.237 )
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    ketamine v Saline Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 24
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of ketamine infusion, which ran for 96 hours to discharge from hospital
    Adverse event reporting additional description
    Patients were visited daily whilst in hospital by the researchers
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    ketamine
    Reporting group description
    		 Patients who received ketamine

    Reporting group title
    Saline Placebo
    Reporting group description
    		 Patients received a saline placebo

    Serious adverse events
    		 ketamine Saline Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 52 (21.15%)
    11 / 52 (21.15%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Hypotensive episode following theatre
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Hallucination, visual
    Additional description: Hallucinations experienced post operatively, mostly thought to be due to opioids
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea infectious
    Additional description: Clostridium difficile confirmed
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
    Additional description: Patient developed respiratory distress post thoracotomy, re-intubated and ventilated.
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung hypoinflation
    Additional description: Lung collapse following thoracotomy for cancer, unable to oxygenate. Death due to respiratory failure.
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
    Additional description: injury post thoracotomy intubation, causing hoarse voice
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: Patient developed renal failure 13 days after starting trial. Renal biopsy showed undetected myeloma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion postoperative
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation postoperative
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 ketamine Saline Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 52 (76.92%)
    34 / 52 (65.38%)
    Nervous system disorders
    Dizziness
    Additional description: Patients who felt lightheaded post-surgery
         subjects affected / exposed
    21 / 52 (40.38%)
    8 / 52 (15.38%)
         occurrences all number
    21
    8
    Nightmare
    Additional description: vivid dreams experienced post-surgery
         subjects affected / exposed
    19 / 52 (36.54%)
    5 / 52 (9.62%)
         occurrences all number
    19
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    25 / 52 (48.08%)
    22 / 52 (42.31%)
         occurrences all number
    25
    22
    Vomiting
    Additional description: post operative vomiting
         subjects affected / exposed
    14 / 52 (26.92%)
    11 / 52 (21.15%)
         occurrences all number
    14
    11
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    16 / 52 (30.77%)
    16 / 52 (30.77%)
         occurrences all number
    16
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2013
    Changes made to the wording in the patient information sheet, patient contact letter and protocol on the request of the surgeon after a patient complained about the term 'chronic' pain
    07 Jan 2014
    Study documents and protocol changed to allow a second study site at St George's Hospital. Recruitment to the VATS study was slow and it was thought that a second site would improve recruitment.

    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
    For support, Contact us.
    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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