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    Clinical Trial Results:
    A randomised, double-blind controlled trial of ketamine versus placebo in conjunction with best pain management in neuropathic pain in cancer patients

    Summary
    EudraCT number
    2007-002080-27
    Trial protocol
    GB  
    Global end of trial date
    05 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    03 May 2019
    First version publication date
    03 May 2019
    Other versions
    Summary report(s)
    JAMA Oncology 2018

    Trial information

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    Trial identification
    Sponsor protocol code
    KPS 2008-01
    Additional study identifiers
    ISRCTN number
    ISRCTN49116945
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    Clinical Research and Development Central Office, West Glasgow Ambulatory Care Hospital, Dalnair St, GLASGOW, United Kingdom, G3 8SW
    Public contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, margaret.fegen@ggc.scot.nhs.uk
    Scientific contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, margaret.fegen@ggc.scot.nhs.uk
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    University Avenue, GLASGOW, United Kingdom, G12 8QQ
    Public contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.ac.uk
    Scientific contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.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
    28 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish whether ketamine given in addition to best standard pain management improves malignant neuropathic pain compared to best standard pain management alone.
    Protection of trial subjects
    As part of the study patients required to attend for additional clinic visits and investigations which would be above those considered to be standard care. The visit schedule and the number and type of investigations were fully explained to patients verbally and in writing via the patient information sheet to ensure patients were fully aware what was entailed in participating in the trial prior to them consenting to the study. The patient information sheet also fully explained the design of the study and that half the patients would receive ketamine and half would receive placebo. The side effects of ketamine were explained in the patient information sheet. All patients were closed monitored throughout the course of the study for adverse events and advised to report any side effects to their study nurse/doctor as they arose.
    Background therapy
    Not Applicable
    Evidence for comparator
    Subsequent human studies have established ketamine as a proven non-competitive antagonist of the NMDA receptor ion channel within the spinal cord. Ketamine blocks the NMDA receptor which subsequently acts by “winding down” and minimising pain transmission; which is particularly of benefit when a hyperexcitability state exists, commonly present in neuropathic pain states. It has a proven role in neuropathic pain and pain secondary to critical limb ischaemia, however its use in neuropathic pain of malignant origin remains unsubstantiated. Through case reports some clinicians who are expert in the use of ketamine have reported good pain relief in situations where best standard approaches have failed. Examination of the use of ketamine in an objective, systematic fashion should enable equity of access to this treatment, if shown to be effective in a randomised controlled trial. A pilot study was completed with s-ketamine, racemic ketamine and placebo in 65 patients. This double-blind randomised placebo controlled trial provides supporting evidence that ketamine may be superior to placebo in malignant neuropathic pain.
    Actual start date of recruitment
    21 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 214
    Worldwide total number of subjects
    214
    EEA total number of subjects
    214
    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)
    149
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study opened to recruitment on 24 April 2009. 214 patients were randomised between 22 May 2009 and 29 April 2014.

    Pre-assignment
    Screening details
    513 patients were assessed for eligibility, 217 were registered, 214 completed run-in and were randomised. The purpose of the run-in period was to stabilise the opioid dose (individually) prior to randomisation to titration. During run-in, no SAEs were reported; 3 patients experienced non-serious AEs: 2x Drowsiness, 1x Extra pyramidal disorder.

    Pre-assignment period milestones
    Number of subjects started
    513 [1]
    Intermediate milestone: Number of subjects
    Registered to run-in: 217
    Number of subjects completed
    214

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Not registered: ineligible: 115
    Reason: Number of subjects
    Not registered: unhappy at option of placebo: 21
    Reason: Number of subjects
    Not registered: declined due to travel issues: 2
    Reason: Number of subjects
    Not registered: conflicting trial: 9
    Reason: Number of subjects
    Not registered: investigator decision: 65
    Reason: Number of subjects
    Not registered: patient too unwell: 29
    Reason: Number of subjects
    Not registered: patient declined for other reasons: 55
    Reason: Number of subjects
    Withdrew during run in: achieved pain control: 2
    Reason: Number of subjects
    Withdrew during run in: Unable to comply: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The trial included a screening period, and a run-in period to allow the dose of opioid analgesia to be optimised prior to randomisation. Those starting the pre-assigment period are those that were screened into the study. The worldwide number enrolled considers randomised patients only due to this being pre-populated from the protocol information supplied to EudraCT.
    Period 1
    Period 1 title
    Titration phase and assessment phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ketamine Hydrochloride
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ketamine Hydrochloride
    Investigational medicinal product code
    CAS: 1867-86-9 (ketamine hydrochloride)
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Titration period: Study drug will be administered under a set-dosing regimen. Each dose will be administered four times daily between the hours of 08:00 and 22:00. Under the dosing regimen study drug will be administered at seven dosing levels. Titration will stop when the McGill Pain Score drops by 5 points or side effects preclude further titration AND it is the opinion of the investigator that clinically meaningful analgesia has been attained. The dose level will be maintained for at least 48 hours before a further increment is made. Table 1: Dose Schedule Days Dose Level Total Daily Dose (mg) 1, 2 1 40 3, 4 2 80 5, 6 3 120 7, 8 4 160 9, 10 5 240 11, 12 6 320 13, 14 7 400 Assessment period: 16 day period of study drug at dose level reached during titration period If patients complete the trial they will remain on either ketamine or placebo for a period of between 17 and 30 days.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Identical placebo capsules marked with the same range of dose levels as Ketamine arm.

    Number of subjects in period 1
    Ketamine Hydrochloride Placebo
    Started
    107
    107
    Completed
    24
    26
    Not completed
    83
    81
         >30% increase in opioid dose (titration phase)
    1
    -
         <5pt improvement in pain during assessment phase
    18
    17
         <5pt improvement in pain during titration phase
    26
    16
         Investigator declared treatment fail (titration)
    31
    41
         >30% increase in opioid dose (assessment phase)
    2
    -
         Investigator declared treatment fail (assessment)
    5
    7
    Period 2
    Period 2 title
    Run-out phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose is reducted from assessment period over a period of 7 days.

    Arm title
    Ketamine Hydrochloride
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ketamine Hydrochloride
    Investigational medicinal product code
    CAS: 1867-86-9 (ketamine hydrochloride)
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose is reducted from assessment period over a period of 7 days.

    Number of subjects in period 2
    Placebo Ketamine Hydrochloride
    Started
    26
    24
    Completed
    48
    49
    Not completed
    2
    0
         No run-out phase
    2
    -
    Joined
    24
    25
         Treatment failure during assessment phase
    24
    25

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Ketamine Hydrochloride Placebo Total
    Number of subjects
    107 107 214
    Age categorical
    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)
    74 75 149
        From 65-84 years
    33 32 65
        85 years and over
    0 0 0
    Age continuous
    Age at registration
    Units: years
        median (standard deviation)
    58 ( 10.12 ) 58 ( 10.91 ) -
    Gender categorical
    Units: Subjects
        Female
    67 66 133
        Male
    40 41 81
    Current/previous analgesics
    Units: Subjects
        Gabapentin
    31 32 63
        Amitriptyline
    17 18 35
        >1 adj. analgesic
    46 43 89
        Pregabalin
    12 12 24
        Declined adj. analgesia
    1 2 3
    Site of primary tumour
    Units: Subjects
        Breast
    30 29 59
        Lung
    15 7 22
        Colorectal
    23 34 57
        Ovarian
    7 2 9
        Bone
    2 1 3
        Skin
    1 3 4
        Other
    29 31 60
    Presence of metastases
    Does the patient have metastases?
    Units: Subjects
        Yes
    24 28 52
        No
    83 79 162
    Prior chemotherapy
    Units: Subjects
        Yes
    89 89 178
        No
    18 18 36
    Prior radiotherapy
    Units: Subjects
        Yes
    50 63 113
        No
    56 44 100
        Missing
    1 0 1
    Prior horomone therapy
    Units: Subjects
        Yes
    25 17 42
        No
    82 90 172
    History of painful neuropathy
    Units: Subjects
        No
    75 74 149
        Yes, not problematic in last 3 months
    3 2 5
        Yes, problematic in last 3 months
    29 31 60
    History of chronic pain
    Units: Subjects
        No
    87 88 175
        Yes, not problematic in past 3 months
    3 2 5
        Yes, problematic in past 3 months
    17 17 34
    History of alcohol or drug dependence
    Units: Subjects
        Yes
    3 5 8
        No
    104 102 206
    Currently alcohol or drug dependent?
    Units: Subjects
        No
    105 106 211
        Missing
    2 1 3
    LANSS status
    Units: Subjects
        Positive
    104 105 209
        Negative
    3 1 4
        Missing
    0 1 1
    Primary method of diagnosis of side of index neuropathic pain
    Units: Subjects
        MRI
    3 4 7
        Clinical
    102 100 202
        Other
    2 3 5
    Index neuropathic pain associated with metastatic site?
    Units: Subjects
        Yes
    2 10 12
        No
    105 97 202
    BTPQ: background pain
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0-3
    4 7 11
        4-6
    33 31 64
        >=7
    47 47 94
        Missing
    23 22 45
    BPTQ: Episodes
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0 (zero)
    10 5 15
        1-5
    33 46 79
        6-10
    20 17 37
        >10
    14 8 22
        Missing
    30 31 61
    BPTQ: Severity
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0-3
    1 2 3
        4-6
    13 12 25
        >=7
    56 65 121
        Missing
    37 28 65
    BPTQ: Episode duration
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        <1 min
    4 9 13
        1-15 mins
    10 21 31
        16-30 mins
    13 13 26
        31-60 mins
    16 7 23
        61-120 mins
    7 8 15
        >120 mins
    18 15 33
        Missing
    39 34 73
    BPTQ: onset to maximum intensity
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Unpredictable
    23 27 50
        <10 sec
    16 17 33
        10 sec - 5 mins
    18 17 35
        6-30 mins
    7 7 14
        31-60 mins
    5 4 9
        >60 mins
    1 1 2
        Missing
    37 34 71
    BPTQ: Predictability
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Never
    41 43 84
        Sometimes
    21 23 44
        Often
    5 3 8
        Almost always
    7 8 15
        Always
    4 2 6
        Missing
    29 28 57
    BPTQ: Use of analgesia
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Every time
    12 13 25
        Most of the time
    13 8 21
        Some of the time
    14 24 38
        Hardly ever
    7 5 12
        Never
    31 30 61
        Missing
    30 27 57
    Breast metastases
    Units: Subjects
        No
    107 105 212
        Yes
    0 2 2
    Lung metastases
    Units: Subjects
        No
    98 98 196
        Yes
    9 9 18
    Colorectal metastases
    Units: Subjects
        No
    106 107 213
        Yes
    1 0 1
    Ovarian metastases
    Units: Subjects
        No
    107 107 214
    Liver metastases
    Units: Subjects
        No
    104 100 204
        Yes
    3 7 10
    Bone metastases
    Units: Subjects
        No
    101 98 199
        Yes
    6 9 15
    Brain metastases
    Units: Subjects
        No
    106 106 212
        Yes
    1 1 2
    Skin metastases
    Units: Subjects
        No
    106 107 213
        Yes
    1 0 1
    Other metastases
    Units: Subjects
        No
    101 96 197
        Yes
    6 11 17
    Baseline McGill sensory pain score
    Units: McGill sensory pain score
        median (standard deviation)
    19 ( 6.18 ) 17 ( 6.32 ) -
    Weight
    Units: kg
        median (standard deviation)
    82.72 ( 19.46 ) 78.45 ( 17.19 ) -
    Global pain score
    VAS (0-10)
    Units: Score
        median (standard deviation)
    7 ( 3.18 ) 6 ( 3.2 ) -
    McGill sensory scale score
    0-33
    Units: Score
        median (standard deviation)
    18 ( 6.22 ) 17 ( 6.59 ) -
    LANSS pain scale score
    0-24
    Units: Score
        median (standard deviation)
    19 ( 3.78 ) 19 ( 3.61 ) -
    Index neuropathic pain worst score in past 24 hours
    VAS (0-10)
    Units: Score
        median (standard deviation)
    8 ( 1.57 ) 8 ( 1.55 ) -
    Subject analysis sets

    Subject analysis set title
    Per protocol: Ketamine
    Subject analysis set type
    Per protocol
    Subject analysis set description
    After blind review of the data, the Chief Investigators defined the per protocol population as all patients who, after randomisation, take at least 80% of the doses of prescribed trial treatment.

    Subject analysis set title
    Per protocol: Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    After blind review of the data, the Chief Investigators defined the per protocol population as all patients who, after randomisation, take at least 80% of the doses of prescribed trial treatment.

    Subject analysis sets values
    Per protocol: Ketamine Per protocol: Placebo
    Number of subjects
    107
    104
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    74
    73
        From 65-84 years
    33
    31
        85 years and over
    0
    0
    Age continuous
    Age at registration
    Units: years
        median (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Current/previous analgesics
    Units: Subjects
        Gabapentin
        Amitriptyline
        >1 adj. analgesic
        Pregabalin
        Declined adj. analgesia
    Site of primary tumour
    Units: Subjects
        Breast
        Lung
        Colorectal
        Ovarian
        Bone
        Skin
        Other
    Presence of metastases
    Does the patient have metastases?
    Units: Subjects
        Yes
        No
    Prior chemotherapy
    Units: Subjects
        Yes
        No
    Prior radiotherapy
    Units: Subjects
        Yes
        No
        Missing
    Prior horomone therapy
    Units: Subjects
        Yes
        No
    History of painful neuropathy
    Units: Subjects
        No
        Yes, not problematic in last 3 months
        Yes, problematic in last 3 months
    History of chronic pain
    Units: Subjects
        No
        Yes, not problematic in past 3 months
        Yes, problematic in past 3 months
    History of alcohol or drug dependence
    Units: Subjects
        Yes
        No
    Currently alcohol or drug dependent?
    Units: Subjects
        No
        Missing
    LANSS status
    Units: Subjects
        Positive
        Negative
        Missing
    Primary method of diagnosis of side of index neuropathic pain
    Units: Subjects
        MRI
        Clinical
        Other
    Index neuropathic pain associated with metastatic site?
    Units: Subjects
        Yes
        No
    BTPQ: background pain
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0-3
        4-6
        >=7
        Missing
    BPTQ: Episodes
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0 (zero)
        1-5
        6-10
        >10
        Missing
    BPTQ: Severity
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        0-3
        4-6
        >=7
        Missing
    BPTQ: Episode duration
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        <1 min
        1-15 mins
        16-30 mins
        31-60 mins
        61-120 mins
        >120 mins
        Missing
    BPTQ: onset to maximum intensity
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Unpredictable
        <10 sec
        10 sec - 5 mins
        6-30 mins
        31-60 mins
        >60 mins
        Missing
    BPTQ: Predictability
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Never
        Sometimes
        Often
        Almost always
        Always
        Missing
    BPTQ: Use of analgesia
    BPTQ = Breakthrough pain questionnaire
    Units: Subjects
        Every time
        Most of the time
        Some of the time
        Hardly ever
        Never
        Missing
    Breast metastases
    Units: Subjects
        No
        Yes
    Lung metastases
    Units: Subjects
        No
        Yes
    Colorectal metastases
    Units: Subjects
        No
        Yes
    Ovarian metastases
    Units: Subjects
        No
    Liver metastases
    Units: Subjects
        No
        Yes
    Bone metastases
    Units: Subjects
        No
        Yes
    Brain metastases
    Units: Subjects
        No
        Yes
    Skin metastases
    Units: Subjects
        No
        Yes
    Other metastases
    Units: Subjects
        No
        Yes
    Baseline McGill sensory pain score
    Units: McGill sensory pain score
        median (standard deviation)
    ( )
    ( )
    Weight
    Units: kg
        median (standard deviation)
    ( )
    ( )
    Global pain score
    VAS (0-10)
    Units: Score
        median (standard deviation)
    ( )
    ( )
    McGill sensory scale score
    0-33
    Units: Score
        median (standard deviation)
    ( )
    ( )
    LANSS pain scale score
    0-24
    Units: Score
        median (standard deviation)
    ( )
    ( )
    Index neuropathic pain worst score in past 24 hours
    VAS (0-10)
    Units: Score
        median (standard deviation)
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Ketamine Hydrochloride
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Ketamine Hydrochloride
    Reporting group description
    -

    Subject analysis set title
    Per protocol: Ketamine
    Subject analysis set type
    Per protocol
    Subject analysis set description
    After blind review of the data, the Chief Investigators defined the per protocol population as all patients who, after randomisation, take at least 80% of the doses of prescribed trial treatment.

    Subject analysis set title
    Per protocol: Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    After blind review of the data, the Chief Investigators defined the per protocol population as all patients who, after randomisation, take at least 80% of the doses of prescribed trial treatment.

    Primary: Malignant neuropathic pain

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    End point title
    Malignant neuropathic pain
    End point description
    To establish whether ketamine given in addition to best standard pain management improves malignant neuropathic pain compared to best standard pain management alone. This is assessed using the sensory component of the McGill Short Form Questionnaire (SF-MPQ). The primary comparison will be in terms of time to treatment “failure” (as defined in 5.1.1) between the study arms. This comparison will be made using the log-rank test. The differences in the “success” rates between the arms at the day 16 assessment point will be estimated and presented together with associated 95% confidence intervals. Treatment failure reasons: - Greater than 30% increase in 24 hour morphine equivalent daily dose - Less than 5 point drop from baseline McGill pain score - Investigator decision due to clinical reasoning or lack of efficacy
    End point type
    Primary
    End point timeframe
    From the end of the run in period (prior to randomisation) to any one of the assessment time points (end of titration period, assessment period: day 1, day 4, day 8, day 12, day 16).
    End point values
    Ketamine Hydrochloride Placebo Per protocol: Ketamine Per protocol: Placebo
    Number of subjects analysed
    107
    107
    107
    104
    Units: Time to treatment failure
    number (not applicable)
        Event (treatment failure)
    83
    81
    83
    78
        Censor (no treatment failure)
    24
    26
    24
    26
    Statistical analysis title
    Time to treatment failure
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.692
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.294
    Notes
    [1] - Cox regression model is performed as a secondary confirmatory analysis of log rank test.
    Statistical analysis title
    Time to treatment failure: per protocol
    Statistical analysis description
    Per protocol comparison, secondary analysis
    Comparison groups
    Per protocol: Placebo v Per protocol: Ketamine
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.594
    Method
    Logrank
    Confidence interval

    Secondary: Initial treatment benefit

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    End point title
    Initial treatment benefit
    End point description
    To compare initial treatment benefit (at day 4 of assessment period of 16 days) using the sensory component of the SF-MPQ.
    End point type
    Secondary
    End point timeframe
    Day 4 of assessment period of 16 days
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Success rate
        number (not applicable)
    34
    39
    Statistical analysis title
    Difference in proportion
    Statistical analysis description
    Ketamine - Placebo
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.471
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Difference in proportion
    Point estimate
    -0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.174
         upper limit
    0.08

    Secondary: Overall pain (global pain score: VAS)

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    End point title
    Overall pain (global pain score: VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    VAS pain score completed daily throughout run in, titration and assessment period.
    End point values
    Ketamine Hydrochloride Placebo Per protocol: Ketamine Per protocol: Placebo
    Number of subjects analysed
    107
    107
    107
    104
    Units: Number of patients
    107
    107
    107
    104
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.917
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Percentage change from baseline (ITT)
    Statistical analysis description
    Change: Number of patients (K=Ketamine, P=Placebo) Increased: K=10, P=17 No change: K=33, P=32 Decreased: K=62, P=50 N.B. 10 patients excluded: 9 patients had baseline score of 0 so not possible to calculate % change; 1 patient had no end of assessment period score.
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Percentage change from baseline (PP)
    Statistical analysis description
    Change: Number of patients (K=Ketamine, P=Placebo) Increased: K=10, P=16 No change: K=33, P=30 Decreased: K=62, P=50 N.B. 201 patients included (105 K; 96 P)
    Comparison groups
    Per protocol: Ketamine v Per protocol: Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.196
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Index site pain (worst pain score: VAS)

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    End point title
    Index site pain (worst pain score: VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    VAS pain score completed daily throughout run in, titration and assessment period.
    End point values
    Ketamine Hydrochloride Placebo Per protocol: Ketamine Per protocol: Placebo
    Number of subjects analysed
    107
    107
    107
    104
    Units: Number of patients
    107
    107
    107
    104
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.155
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Percentage change from baseline (ITT)
    Statistical analysis description
    Change: Number of patients (K=Ketamine, P=Placebo) Increased: K=12, P=13 No change: K=22, P=21 Decreased: K=73, P=73
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.984
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Percentage change from baseline (PP)
    Statistical analysis description
    Change: Number of patients (K=Ketamine, P=Placebo) Increased: K=12, P=12 No change: K=22, P=21 Decreased: K=73, P=71
    Comparison groups
    Per protocol: Ketamine v Per protocol: Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.999
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Patient distress

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    End point title
    Patient distress
    End point description
    End point type
    Secondary
    End point timeframe
    NCCN Distress Thermometer completed at end of run in period (prior to randomisation) and day 1, 4, 8, 12 and 16 of assessment period.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Number of patients
    107
    107
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.635
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of Life (EuroQol thermometer)

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    End point title
    Quality of Life (EuroQol thermometer)
    End point description
    End point type
    Secondary
    End point timeframe
    EuroQoL Thermometer completed at end of run in period (prior to randomisation) and day 1, 4, 8, 12 and 16 of assessment period.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Number of patients
    107
    107
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.893
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Anxiety (HADS)

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    End point title
    Anxiety (HADS)
    End point description
    End point type
    Secondary
    End point timeframe
    HADS completed at end of run in period (prior to randomisation) and day 1, 4, 8, 12 and 16 of assessment period.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Number of patients
    107
    107
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.647
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Depression (HADS)

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    End point title
    Depression (HADS)
    End point description
    End point type
    Secondary
    End point timeframe
    HADS completed at end of run in period (prior to randomisation) and day 1, 4, 8, 12 and 16 of assessment period.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Number of patients
    107
    107
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.663
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Daily opioid requirement (MEDD)

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    End point title
    Daily opioid requirement (MEDD)
    End point description
    MEDD: morphine equivalent daily dose
    End point type
    Secondary
    End point timeframe
    Over titration and assessment periods
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Average daily MEDD
        arithmetic mean (standard deviation)
    75.95 ( 236.95 )
    73.74 ( 216.66 )
    Statistical analysis title
    Area under curve analysis
    Statistical analysis description
    AUC calculated over the assessment/titration period, divided by number of days on assessment/titration and with the baseline value subtracted.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.585
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quantitative sensory testing: Brush

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    End point title
    Quantitative sensory testing: Brush
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Brush
        Increased
    10
    9
        Reduced
    9
    8
        No difference than control
    6
    11
        Missing
    82
    79
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - detection threshold

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    End point title
    Quantitative sensory testing: Von Frey filaments - detection threshold
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Detection threshold
        Increased
    5
    9
        Reduced
    19
    17
        No difference than control
    8
    7
        Missing
    75
    74
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - pain threshold

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    End point title
    Quantitative sensory testing: Von Frey filaments - pain threshold
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Pain threshold
        Increased
    12
    17
        Reduced
    6
    8
        No difference than control
    14
    7
        Missing
    75
    75
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - cool

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    End point title
    Quantitative sensory testing: Von Frey filaments - cool
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Cool
        Increased
    14
    10
        Reduced
    11
    20
        No difference than control
    5
    3
        Missing
    77
    74
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - warm

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    End point title
    Quantitative sensory testing: Von Frey filaments - warm
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Warm
        Increased
    8
    8
        Reduced
    15
    22
        No difference than control
    7
    3
        Missing
    77
    74
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - pin prick

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    End point title
    Quantitative sensory testing: Von Frey filaments - pin prick
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Pin prick
        Increased
    15
    14
        Reduced
    11
    12
        No difference than control
    5
    7
        Missing
    76
    74
    No statistical analyses for this end point

    Secondary: Quantitative sensory testing: Von Frey filaments - wind up

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    End point title
    Quantitative sensory testing: Von Frey filaments - wind up
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Secondary
    End point timeframe
    Quantitative sensory testing (QST) at the end of the assessment period. Summarising test area compared to control area.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Wind up
        Increased
    14
    19
        Reduced
    10
    8
        No difference than control
    6
    5
        Missing
    77
    75
    No statistical analyses for this end point

    Secondary: QST change in sensation: Brush

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    End point title
    QST change in sensation: Brush
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    6
    9
        No change
    14
    16
        Normal to abnormal
    3
    0
        Missing
    84
    82
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.219
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: QST change in sensation: detection threshold

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    End point title
    QST change in sensation: detection threshold
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    5
    4
        No change
    25
    23
        Normal to abnormal
    1
    4
        Missing
    76
    76
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.411
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: QST change in sensation: pain threshold

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    End point title
    QST change in sensation: pain threshold
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    9
    4
        No change
    21
    23
        Normal to abnormal
    0
    4
        Missing
    77
    76
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035 [2]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Not adjusted for multiple testing. Adjusted p=0.245

    Secondary: QST change in sensation: cool

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    End point title
    QST change in sensation: cool
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    1
    1
        No change
    26
    29
        Normal to abnormal
    2
    2
        Missing
    78
    75
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.93
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: QST change in sensation: warm

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    End point title
    QST change in sensation: warm
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    4
    3
        No change
    21
    27
        Normal to abnormal
    3
    2
        Missing
    79
    75
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.863
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: QST change in sensation: pin prick

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    End point title
    QST change in sensation: pin prick
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    4
    6
        No change
    22
    24
        Normal to abnormal
    2
    2
        Missing
    79
    75
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.728
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: QST change in sensation: wind-up

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    End point title
    QST change in sensation: wind-up
    End point description
    QST was introduced approximately 1 year after study open. Only patients completing the 16 day assessment period (i.e. "responders") can be included in the change at end of assessment period analysis. Therefore the comparison between arms does not reflect the initial randomisation and is therefore biased and difficult to interpret. [Abnormal sensation is increased or reduced sensation in test area compared to control area; normal sensation is no difference between test and control areas]
    End point type
    Secondary
    End point timeframe
    Summarising change from abnormal sensation in test areas compared to control areas to normal sensation, and vice-versa, between end of run-in and day 16 assessment.
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Change in sensation
        Abnormal to normal
    5
    4
        No change
    22
    27
        Normal to abnormal
    1
    0
        Missing
    79
    76
    Statistical analysis title
    Mann-Whitney U test
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.856
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Malignant neuropathic pain (exploratory definition of treatment failure)

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    End point title
    Malignant neuropathic pain (exploratory definition of treatment failure)
    End point description
    As per primary endpoint but treatment failure based on opioid dose includes the prescribed background opioid dose as per primary endpoint, and ALSO recorded breakthrough (PRN) dose.
    End point type
    Other pre-specified
    End point timeframe
    As per primary endpoint
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Time to treatment failure
    number (not applicable)
        Event (Treatment failure)
    83
    81
        Censor (no treatment failure)
    24
    26
    Statistical analysis title
    Time to treatment failure
    Statistical analysis description
    As per primary analysis with updated defintion of treatment failure.
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.694
    Method
    Logrank
    Confidence interval

    Post-hoc: Break through pain questionnaire

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    End point title
    Break through pain questionnaire
    End point description
    Only patients who complete the 16 day assessment period (‘responders’) can be included in the end of assessment period analysis. Note also that this restriction to "responders" means that the comparison between the arms does not reflect the initial randomisation and is therefore biased and difficult to interpret.
    End point type
    Post-hoc
    End point timeframe
    At end of assessment period
    End point values
    Ketamine Hydrochloride Placebo
    Number of subjects analysed
    107
    107
    Units: Patients
    107
    107
    Statistical analysis title
    Mann-whitney U test: Background pain
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.523
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test: Episodes
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.506
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test: Severity
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.79
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test:Episode duration
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.574
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test: Onset to max intensity
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.669
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test: Predictability
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.857
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Mann-whitney U test: Use of analgesia
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.38
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Background pain
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.399
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Episodes of pain
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.697
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Severity of pain
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.735
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Episode duration
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.589
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Onset to max intensity
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.909
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Prediction of flare-up
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.999
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change from baseline: Use of analgesia
    Comparison groups
    Placebo v Ketamine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.889
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Post-hoc: McGill pain score

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    End point title
    McGill pain score
    End point description
    End point type
    Post-hoc
    End point timeframe
    Baseline (end of run-in) and end of assessment period.
    End point values
    Ketamine Hydrochloride Placebo Per protocol: Ketamine Per protocol: Placebo
    Number of subjects analysed
    94 [3]
    87 [4]
    94
    87
    Units: Number of patients
    94
    106
    94
    87
    Notes
    [3] - 13 patients had only a baseline score
    [4] - 19 patients had only a baseline score 1 patient had baseline score of 0
    Statistical analysis title
    Percentage change from baseline (ITT)
    Statistical analysis description
    Change: Number of patients (K=Ketamine, P=Placebo) Increase: K=24, P=13 No change: K=5, P=2 Decreased: K=65, P=72
    Comparison groups
    Ketamine Hydrochloride v Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.039 [5]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Unadjusted. Adjusted p-value=0.118
    Statistical analysis title
    Percentage change from baseline (PP)
    Comparison groups
    Per protocol: Ketamine v Per protocol: Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Post-hoc
    Analysis type
    superiority [6]
    P-value
    = 0.039 [7]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Change: Number of patients (K=Ketamine, P=Placebo) Increase: K=24, P=13 No change: K=5, P=2 Decreased: K=65, P=72
    [7] - Unadjusted. Adjusted p-value=0.118

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were recorded from study entry throughout the study period and for at least 30 days after discontinuation of study medication. All adverse events were followed until resolution.
    Adverse event reporting additional description
    Specifically, opioid toxicity was recorded at the end of the Run-In Period. For each subject, the worst grade of each AE during each resporting period was recorded hence the number of subjects and number of occurrences is the same. For the serious adverse events "causally related" has been defined as a relationship of at least 'Possible'
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Ketamine Hydrochloride (Titration)
    Reporting group description
    -

    Reporting group title
    Placebo (Titration)
    Reporting group description
    -

    Reporting group title
    Ketamine Hydrochloride (Assessment)
    Reporting group description
    -

    Reporting group title
    Placebo (Assessment)
    Reporting group description
    -

    Reporting group title
    Ketamine Hydrochloride (Run-out)
    Reporting group description
    -

    Reporting group title
    Placebo (Run-out)
    Reporting group description
    -

    Serious adverse events
    Ketamine Hydrochloride (Titration) Placebo (Titration) Ketamine Hydrochloride (Assessment) Placebo (Assessment) Ketamine Hydrochloride (Run-out) Placebo (Run-out)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 107 (3.74%)
    3 / 107 (2.80%)
    0 / 49 (0.00%)
    4 / 50 (8.00%)
    4 / 45 (8.89%)
    2 / 44 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    2
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Alkaline phosphatase
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALT
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GGT
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AST
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular arrhythmia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurology other
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Infection
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    4 / 45 (8.89%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstruction GU
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Ketamine Hydrochloride (Titration) Placebo (Titration) Ketamine Hydrochloride (Assessment) Placebo (Assessment) Ketamine Hydrochloride (Run-out) Placebo (Run-out)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 107 (61.68%)
    37 / 107 (34.58%)
    13 / 49 (26.53%)
    14 / 50 (28.00%)
    16 / 45 (35.56%)
    7 / 44 (15.91%)
    General disorders and administration site conditions
    Nightmare
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 107 (5.61%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    6
    0
    0
    0
    0
    Constitutional symptoms
         subjects affected / exposed
    4 / 107 (3.74%)
    1 / 107 (0.93%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    1
    1
    1
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    6
    2
    0
    0
    0
    0
    Fever
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    1 / 107 (0.93%)
    3 / 107 (2.80%)
    2 / 49 (4.08%)
    4 / 50 (8.00%)
    1 / 45 (2.22%)
    1 / 44 (2.27%)
         occurrences all number
    1
    3
    2
    4
    1
    1
    Pain
         subjects affected / exposed
    10 / 107 (9.35%)
    11 / 107 (10.28%)
    0 / 49 (0.00%)
    4 / 50 (8.00%)
    2 / 45 (4.44%)
    2 / 44 (4.55%)
         occurrences all number
    10
    11
    0
    4
    2
    2
    Rigors/ chills
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Immune system disorders
    Allergic Reaction
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 107 (2.80%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Investigations
    Alkaline phosphatase
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    ALT
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    AST
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    GGT
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Supraventricular arrythmia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    5 / 107 (4.67%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    5
    2
    0
    2
    0
    0
    Hallucination
         subjects affected / exposed
    3 / 107 (2.80%)
    3 / 107 (2.80%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    3
    0
    1
    0
    0
    Cognitive disturbance
         subjects affected / exposed
    13 / 107 (12.15%)
    4 / 107 (3.74%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
    2 / 45 (4.44%)
    0 / 44 (0.00%)
         occurrences all number
    13
    4
    4
    1
    2
    0
    Dizziness
         subjects affected / exposed
    32 / 107 (29.91%)
    6 / 107 (5.61%)
    6 / 49 (12.24%)
    1 / 50 (2.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences all number
    32
    6
    6
    1
    1
    0
    Involuntary movement
         subjects affected / exposed
    3 / 107 (2.80%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences all number
    3
    1
    0
    0
    1
    0
    Mood altered
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    Neurology other
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    6
    2
    0
    0
    0
    0
    Sensory neuropathy
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Personality change
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    4 / 107 (3.74%)
    3 / 107 (2.80%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    3
    0
    0
    0
    0
    Speech impairment
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vasovagal episode
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Ocular
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    4 / 107 (3.74%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    1
    0
    2
    0
    0
    Dry mouth
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    GI
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Heartburn
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Mucositis
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    8 / 107 (7.48%)
    9 / 107 (8.41%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences all number
    8
    9
    1
    4
    1
    0
    Obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 107 (1.87%)
    2 / 107 (1.87%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences all number
    2
    2
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Sweating
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Obstruction GU
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary frequency
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal other
         subjects affected / exposed
    3 / 107 (2.80%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    0
    Infections and infestations
    Nasal/ paranasal reaction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2009
    *Protocol clarifications *Addition of Quantitative Sensory Testing (QST) Questionnaire *Addition of new sites (Royal Lancaster / St John's Hospice) *Removal of site (Royal Brompton Hospital) *Update to Patient Information Sheet/Consent Form and GP Letter
    25 Mar 2010
    *Addition of a site (St Catherine's Hospice)
    08 Apr 2010
    Restart after Temporary Halt
    25 Jun 2010
    *Addition of a Site (St George's Hospital)
    27 Oct 2010
    *Eligibility criteria amendment to state that patients need to have been offered a trial of an adjuvant analgesic. Clarification that written informed consent must be obtained within 28 days prior to study entry. *Administrative changes updating participating sites and change in contact details. *Typo corrected in section 7.2.2 Secondary efficacy analysis (weeks should read days) *Changes to patient information sheet to inform patients that the titration phase could possibly last more than 14 days and also that the number of trial sites has changes *Changes to the consent form to remove ‘Centre No’ as centre numbers are not used in this study (this has been changed to ‘Site’ *Administrative changes updating participating sites and change in contact details. *Updated patient information sheet and consent form
    06 Jan 2011
    *Addition of Site (Nottingham)
    11 Feb 2011
    Temporary Halt of Study *Recruitment stopped 10/02/2010 Shortage of IMP meant that no new patients could be recruitmed into the study in order that the patient already on treatment could continue until completion
    18 Feb 2013
    *Removal of a site (St George's Hospital)
    11 Apr 2013
    *Removal of a site (St Catherine's Hospice)

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Feb 2010
    Interruption due to a shortage in IMP which resulted in no new patients being able to start treatment in order that patients currently on study could complete treatment
    22 Feb 2010

    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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    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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