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    Clinical Trial Results:
    A double blind, randomized, placebo-controlled, parallel group study of Sativex oromucosal spray (Sativex®; Nabiximols) as adjunctive therapy in relieving uncontrolled persistent chronic pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy.

    Summary
    EudraCT number
    2009-016065-29
    Trial protocol
    CZ   GB   DE   PL   BG   HU   RO  
    Global end of trial date
    24 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2018
    First version publication date
    30 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GWCA0962
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01361607
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GW Pharmaceuticals Ltd.
    Sponsor organisation address
    Sovereign House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom,
    Public contact
    GW Pharmaceuticals Ltd. Switchboard., GW Pharmaceuticals Ltd., +44 1980557000, medinfo@gwpharm.com
    Scientific contact
    GW Pharmaceuticals Ltd. Switchboard., GW Pharmaceuticals Ltd., +44 1980557000, medinfo@gwpharm.com
    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
    02 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Sativex® (nabiximols), when used as an adjunctive (not breakthrough) measure, compared with placebo in relieving uncontrolled persistent chronic pain in participants with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy.
    Protection of trial subjects
    This study was conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practice, the principles of the Declaration of Helsinki, and with the laws of the countries in which the study was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 May 2011
    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: 44
    Country: Number of subjects enrolled
    United States: 120
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Poland: 96
    Country: Number of subjects enrolled
    Romania: 67
    Worldwide total number of subjects
    399
    EEA total number of subjects
    269
    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)
    266
    From 65 to 84 years
    130
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants had been clinically diagnosed with advanced cancer for which there was no known curative therapy, and had a clinical diagnosis of cancer related pain, which was not wholly alleviated by their current optimized opioid treatment. Two participants randomized to Sativex did not receive any study drug.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer
    Blinding implementation details
    Study drug was provided in 10 mL Type I amber glass vials labeled with the GW name, study code, participant number, visit number and the expiry date. The identity of the study drug assigned to participants was held by the interactive voice response system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sativex
    Arm description
    Sativex was self-administered by participants as a 100 microliter (μL) oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).
    Arm type
    Experimental

    Investigational medicinal product name
    Sativex®
    Investigational medicinal product code
    Other name
    Nabiximols
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Sativex was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day for 5 weeks. Sativex oromucosal spray contained THC (27 mg/milliliter [mL]):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.

    Arm title
    Placebo (GA-0034)
    Arm description
    Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (GA-0034)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.

    Number of subjects in period 1
    Sativex Placebo (GA-0034)
    Started
    200
    199
    Received at least 1 dose of study drug
    198
    199
    Safety Population
    199
    198
    Intent to Treat (ITT) Population
    198
    199
    Completed
    136
    158
    Not completed
    64
    41
         Met withdrawal criteria
    1
    1
         Physician decision
    5
    3
         Adverse event
    38
    29
         Consent withdrawn by subject
    19
    8
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sativex
    Reporting group description
    Sativex was self-administered by participants as a 100 microliter (μL) oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).

    Reporting group title
    Placebo (GA-0034)
    Reporting group description
    Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.

    Reporting group values
    Sativex Placebo (GA-0034) Total
    Number of subjects
    200 199 399
    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)
    133 133 266
        From 65-84 years
    65 65 130
        85 years and over
    2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.0 ± 11.0 59.6 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    94 102 196
        Male
    106 97 203

    End points

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    End points reporting groups
    Reporting group title
    Sativex
    Reporting group description
    Sativex was self-administered by participants as a 100 microliter (μL) oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).

    Reporting group title
    Placebo (GA-0034)
    Reporting group description
    Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 5 weeks. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.

    Subject analysis set title
    Sativex (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to. One participant randomized to Sativex received placebo on Day 22 but was analyzed as Sativex-treated.

    Subject analysis set title
    Placebo (GA-0034) (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 efficacy endpoint. Participants were analyzed according to the treatment group they were randomized to. One participant randomized to placebo received Sativex on Day 1 but was analyzed as placebo-treated.

    Primary: Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment

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    End point title
    Percent Improvement From Baseline In Mean NRS Average Pain At End Of Treatment
    End point description
    Participants indicated level of pain in the last 24 hours on an 11-point Numerical Rating Scale (NRS), where a score of 0 was “no pain” and 10 was “pain as bad as you can imagine”. Baseline = mean score from first day of 3-day eligibility period through to the day before first dose of study drug. End of Treatment = mean score over last (up to) 7 days to the final pain score at End of Treatment or up until Day 35, whichever is earlier, or final score available (prematurely terminated). Percentage improvement from baseline (Imp%) was calculated as: Imp% = (Baseline pain NRS mean - End of Treatment pain NRS mean)/Baseline pain NRS mean * 100. For participants who died or withdrew due to disease progression, Imp% values were used. For participants who died or withdrew, unrelated to disease progression, before end of Week 5 (no diary data from Day 33 onwards), Imp% was zero for participants whose Imp% value was positive and it was Imp% for participants whose Imp% value was not positive.
    End point type
    Primary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: percent improvement
        median (inter-quartile range (Q1-Q3))
    7.2 (0.0 to 29.4)
    9.5 (0.0 to 34.5)
    Statistical analysis title
    Percent Improvement In Mean NRS Average Pain
    Statistical analysis description
    Imp% = (Baseline pain NRS mean - End of Treatment pain NRS mean)/Baseline pain NRS mean * 100. For participants who died or withdrew due to disease progression, Imp% values were used. For participants who died or withdrew unrelated to disease progression before end of Week 5 (no diary data from Day 33 onwards), Imp% was zero for participants whose Imp% value was positive and it was Imp% for participants whose Imp% value was not positive.
    Comparison groups
    Sativex (ITT Population) v Placebo (GA-0034) (ITT Population)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2735
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (final values)
    Point estimate
    -1.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.19
         upper limit
    1.5

    Secondary: Change From Baseline In Mean NRS Average Pain At End Of Treatment

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    End point title
    Change From Baseline In Mean NRS Average Pain At End Of Treatment
    End point description
    Participants indicated the level of pain experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated “no pain” and a score of 10 indicated “pain as bad as you can imagine.” Change in mean NRS average pain was calculated as: End of Treatment NRS average pain score- Baseline NRS average pain score. A negative value indicates an improvement in average pain score from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.9 ± 1.5
    -1.0 ± 1.5
    No statistical analyses for this end point

    Secondary: Change From Baseline In Mean NRS Worst Pain At End Of Treatment

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    End point title
    Change From Baseline In Mean NRS Worst Pain At End Of Treatment
    End point description
    Participants indicated the level of worst pain experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated “no pain” and a score of 10 indicated “pain as bad as you can imagine.” Change in mean NRS worst pain was calculated as: End of Treatment NRS worst pain score - Baseline NRS worst pain score. A negative value indicates an improvement in worst pain score from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.0 ± 1.7
    -1.2 ± 1.6
    No statistical analyses for this end point

    Secondary: Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment

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    End point title
    Change From Baseline In Mean Sleep Disruption NRS At End Of Treatment
    End point description
    Participants indicated the level of sleep disruption experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated “did not disrupt sleep” and a score of 10 indicated “completely disrupted (unable to sleep at all).” Change in mean sleep disruption NRS was calculated as: End of Treatment sleep disruption NRS score - Baseline sleep disruption NRS score. A negative value indicates an improvement in sleep disruption score from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.9 ± 1.8
    -1.1 ± 1.7
    No statistical analyses for this end point

    Secondary: Subject Global Impression Of Change At Last Visit (Up To Day 36)

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    End point title
    Subject Global Impression Of Change At Last Visit (Up To Day 36)
    End point description
    The Subject Global Impression of Change (SGIC) was used to assess the overall status of the participant related to their cancer pain, with the markers “very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse”. The SGIC was assessed at Day 36 or at which a participant’s last evaluation is performed, such as in the case of early termination. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36.
    End point type
    Secondary
    End point timeframe
    Last visit (up to Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    175
    184
    Units: participants
        Very Much Improved
    19
    11
        Much Improved
    36
    35
        Slightly Improved
    64
    51
        No Change
    38
    67
        Slightly Worse
    13
    13
        Much Worse
    5
    6
        Very Much Worse
    0
    1
    No statistical analyses for this end point

    Secondary: Physician Global Impression Of Change At Last Visit (Up To Day 36)

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    End point title
    Physician Global Impression Of Change At Last Visit (Up To Day 36)
    End point description
    The Physician Global Impression of Change (PGIC) was used by the treating physician (investigator/sub-investigator) to assess if there was any change in the general functional abilities of the participant since prior to commencement of study medication, with the markers: “very much worse, much worse, slightly worse, no change, slightly improved, much improved, very much improved”. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    176
    184
    Units: participants
        Very Much Improved
    13
    11
        Much Improved
    37
    32
        Slightly Improved
    62
    48
        No Change
    41
    78
        Slightly Worse
    18
    10
        Much Worse
    5
    4
        Very Much Worse
    0
    1
    No statistical analyses for this end point

    Secondary: Patient Satisfaction Questionnaire At Last Visit (Up To Day 36)

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    End point title
    Patient Satisfaction Questionnaire At Last Visit (Up To Day 36)
    End point description
    The Patient Satisfaction Questionnaire (PSQ) was used to assess level of satisfaction of the participant with the study drug, with the markers “extremely satisfied, very satisfied, slightly satisfied, neutral, slightly dissatisfied, very dissatisfied, extremely dissatisfied”. Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    175
    184
    Units: participants
        Extremely Satisfied
    18
    8
        Very Satisfied
    34
    43
        Slightly Satisfied
    55
    54
        Neutral
    35
    52
        Slightly Dissatisfied
    13
    15
        Very Dissatisfied
    15
    6
        Extremely Dissatisfied
    5
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment

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    End point title
    Change From Baseline In Daily Total Opioid Use (Morphine Equivalent) At End Of Treatment
    End point description
    The total daily opioid use (in morphine equivalence) was the sum of morphine equivalence of daily maintenance dose and break-through dose. Change in daily total opioid use was calculated as: End of Treatment daily total opioid use - Baseline daily total opioid use. A negative value indicates a decrease in use from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    -6.5 ± 53.9
    2.3 ± 42.5
    No statistical analyses for this end point

    Secondary: Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment

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    End point title
    Change From Baseline In Daily Maintenance Opioid Dose (Morphine Equivalent) At End of Treatment
    End point description
    The prescribed daily quantity of opioid maintenance dose was calculated as the product of dose per use and daily frequency of use. Participants were asked: “Have you used your maintenance dose painkiller today as prescribed?” If the participant answered “No” to the question, the daily opioid maintenance dose usage on that day was set to 0. Change in daily maintenance opioid dose was calculated as: End of Treatment daily maintenance opioid dose - Baseline daily maintenance opioid dose. A negative value indicates a decrease in dose from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    197
    199
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    -1.5 ± 38.2
    1.9 ± 34.3
    No statistical analyses for this end point

    Secondary: Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment

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    End point title
    Change From Baseline In Daily Break-through Opioid Dose (Morphine Equivalent) At End Of Treatment
    End point description
    Daily break-through opioid dose usage was calculated as the product of prescribed dose per use, and the number of uses per day. If participants took more than 1 different break-through opioid for more than 1 day, the sum of morphine equivalence dose usages for each break-through opioid was calculated for the summary. Change in daily break-through opioid dose was calculated as: End of Treatment daily break-through opioid dose - Baseline daily maintenance opioid dose. A negative value indicates a decrease in dose from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatment (Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    198
    199
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    -4.4 ± 27.7
    0.5 ± 20.5
    No statistical analyses for this end point

    Secondary: Change From Baseline In NRS Constipation At Last Visit (Up To Day 36)

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    End point title
    Change From Baseline In NRS Constipation At Last Visit (Up To Day 36)
    End point description
    Participants indicated level of constipation on an 11-point NRS, where a score of 0 was “no constipation”, and 10 was “constipation as bad as you can imagine.” Last visit refers to the last visit that a participant completed the assessment; this could be either Day 22 or Day 36. Change in NRS constipation score was calculated as: Last Visit NRS constipation score - Baseline NRS constipation score. A negative value indicates improvement in condition from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Last Visit (up to Day 36)
    End point values
    Sativex (ITT Population) Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    174
    184
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.4 ± 2.6
    -0.6 ± 2.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 43 post-randomization
    Adverse event reporting additional description
    The Safety Population included all participants receiving at least 1 dose of study drug. Per the Statistical Analyses Plan, if a participant randomized to placebo ever took a Sativex dose, the participant was analyzed as Sativex-treated in the Safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sativex (Safety Population)
    Reporting group description
    The Safety Population included all participants receiving at least 1 dose of study drug. One participant randomized to placebo received Sativex on Day 1 but was analyzed as Sativex-treated. One participant randomized to Sativex received placebo on Day 22 but was analyzed as Sativex-treated.

    Reporting group title
    Placebo (GA-0034) (Safety Population)
    Reporting group description
    The Safety Population included all participants receiving at least 1 dose of study drug. One participant randomized to placebo received Sativex on Day 1 but was analyzed as Sativex-treated. One participant randomized to Sativex received placebo on Day 22 but was analyzed as Sativex-treated.

    Serious adverse events
    Sativex (Safety Population) Placebo (GA-0034) (Safety Population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 199 (17.59%)
    44 / 198 (22.22%)
         number of deaths (all causes)
    19
    24
         number of deaths resulting from adverse events
    19
    24
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrosarcoma metastatic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningioma malignant
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    23 / 199 (11.56%)
    31 / 198 (15.66%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 31
         deaths causally related to treatment / all
    0 / 17
    0 / 23
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         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
    Dyspnoea
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminemia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sativex (Safety Population) Placebo (GA-0034) (Safety Population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 199 (29.65%)
    45 / 198 (22.73%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 199 (8.04%)
    9 / 198 (4.55%)
         occurrences all number
    18
    9
    Somnolence
         subjects affected / exposed
    23 / 199 (11.56%)
    8 / 198 (4.04%)
         occurrences all number
    24
    8
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 199 (4.02%)
    13 / 198 (6.57%)
         occurrences all number
    8
    13
    Nausea
         subjects affected / exposed
    19 / 199 (9.55%)
    16 / 198 (8.08%)
         occurrences all number
    20
    17
    Vomiting
         subjects affected / exposed
    17 / 199 (8.54%)
    13 / 198 (6.57%)
         occurrences all number
    19
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2010
    * Change in the primary analysis variable from the 30% responder analysis to the continuous responder analysis with resulting increase in sample size from 370 to 380 participants. * Removal of Quality of Life assessments from the protocol as they were not sensitive enough to detect a difference between Sativex and placebo but did add excessive burden to participants. These were replaced with 2 simple questions asked to participants at each study visit about a) their level of constipation and b) their satisfaction with their medicine and recorded on a simple 0-10 NRS scale. * Reinforcing the point that the protocol included a study population which was one of terminally ill, advanced cancer patients and that Sativex was to be dosed twice-daily, not as-needed. * The dosing paradigm was described more specifically. * The definition of optimized therapy was improved and a minimum threshold level of morphine equivalence (>90 mg transdermal drug delivery) was added for those participants where it was deemed clinically inappropriate to increase their dose because no further efficacy benefit was expected. * How rescue analgesia was addressed in the statistical analysis was clarified. * Various updates to bring in line with the current protocol template, internal safety operating procedures, and any updated legislation. * The PGIC questionnaire was updated. * Safety follow-up period extended to 2 weeks.
    16 Jul 2012
    * Wording in Section 4.1.1 was amended to make it clearer for the reader with regards to the length of the eligibility period, changes to opioids during this period, and potential rescreening of participants. * The protocol was also updated to reflect an amended and expanded non-linear ‘morphine equivalence’ conversion scheme for methadone doses. * Wording where needed was amended to clarify that regular around the clock dosing with immediate-release opioids as a maintenance dose, was ideally to be every 4 hours. * Section 8.6, Access to Blinded Treatment Assignment, was updated to clarify to investigators that it was acceptable to unblind prior to contacting GW, but where possible, GW encouraged communication first. * The wording in Section 9.1.8, Clinical Laboratory Sampling, was revised to clarify how the THC test at Screening was performed and that there was a secondary test to confirm any initial positive THC tests. * Section 11.7, Follow up Procedures for Adverse Events, was updated following Food and Drug Administration guidance to clarify that GW may have needed to follow up with the center on certain adverse events of special medical interest, in particular those associated with abuse potential or addiction.
    14 Mar 2013
    * An annex to the protocol was issued to describe the methodology for identifying and evaluating clinical study adverse event data through systematic categorization, tabulation, and analysis that can illuminate an abuse potential signal. This impacted study procedures for United States and United Kingdom centers from the point of implementation onwards.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28785408
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