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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
    2009-016064-36
    Trial protocol
    CZ   PL   BE   GB   DE   RO   HU   EE   LV   LT   BG  
    Global end of trial date
    02 Jul 2015

    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
    GWCA0958
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01262651
    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, CB24 9BZ
    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
    27 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2015
    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
    25 Nov 2010
    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: 45
    Country: Number of subjects enrolled
    United States: 129
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czech Republic: 50
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 37
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Romania: 48
    Worldwide total number of subjects
    397
    EEA total number of subjects
    268
    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)
    264
    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.

    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 twice daily as a 100 μL oromucosal spray, up to a maximum of 10 sprays per day for 5 weeks. Sativex oromucosal spray contained THC (27 mg/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
    199
    198
    Safety Population
    199
    198
    Intent to Treat (ITT) Population
    199
    198
    Received at least 1 dose of study drug
    199
    198
    Completed
    141
    150
    Not completed
    58
    48
         Physician decision
    2
    2
         Met Withdrawal Criteria
    1
    -
         Consent withdrawn by subject
    15
    11
         Adverse Events
    40
    35

    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
    199 198 397
    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)
    132 132 264
        From 65-84 years
    66 64 130
        85 years and over
    1 2 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.2 ± 12.0 60.7 ± 11.1 -
    Gender categorical
    Units: Subjects
        Female
    88 95 183
        Male
    111 103 214

    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.

    Primary: Percent Improvement From Baseline In Mean Numerical Rating Scale (NRS) Average Pain At End Of Treatment

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    End point title
    Percent Improvement From Baseline In Mean Numerical Rating Scale (NRS) Average Pain At End Of Treatment
    End point description
    Participants indicated level of pain in the last 24 hours on an 11-point 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 if participant 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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: Percent Improvement
        median (inter-quartile range (Q1-Q3))
    10.7 (0.0 to 30.0)
    4.5 (-2.9 to 25.7)
    Statistical analysis title
    Percent Improvement In Mean NRS Average Pain Score
    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 if participant Imp% value was positive and it was Imp% for participants whose Imp% value was not positive.
    Comparison groups
    Sativex v Placebo (GA-0034)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0854
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (final values)
    Point estimate
    3.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    8.16

    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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: Unit of a scale
        arithmetic mean (standard deviation)
    -0.8 ± 1.4
    -0.6 ± 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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: Unit on a scale
        arithmetic mean (standard deviation)
    -0.9 ± 1.4
    -0.8 ± 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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.8 ± 1.7
    -0.5 ± 1.6
    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 Placebo (GA-0034)
    Number of subjects analysed
    172
    179
    Units: Participants
        Very Much Improved
    5
    3
        Much Improved
    34
    26
        Slightly Improved
    60
    55
        No Change
    56
    72
        Slightly Worse
    9
    13
        Much Worse
    6
    6
        Very Much Worse
    2
    4
    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 Placebo (GA-0034)
    Number of subjects analysed
    174
    181
    Units: Participants
        Very Much Improved
    6
    3
        Much Improved
    37
    25
        Slightly Improved
    56
    50
        No Change
    41
    75
        Slightly Worse
    25
    19
        Much Worse
    7
    5
        Very Much Worse
    2
    4
    No statistical analyses for this end point

    Secondary: Patient Satisfaction Questionnaire At Last Visit (Up To End Of Treatment)

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    End point title
    Patient Satisfaction Questionnaire At Last Visit (Up To End Of Treatment)
    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 Placebo (GA-0034)
    Number of subjects analysed
    171
    179
    Units: Participants
        Extremely Satisfied
    7
    3
        Very Satisfied
    42
    38
        Slightly Satisfied
    42
    37
        Neutral
    46
    63
        Slightly Dissatisfied
    22
    20
        Very Dissatisfied
    11
    13
        Extremely Dissatisfied
    1
    5
    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 equivalents 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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    0.3 ± 34.7
    0.6 ± 44.8
    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 Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    0.2 ± 20.9
    -1.3 ± 38.7
    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 equivalents 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, Last Visit (Day 36)
    End point values
    Sativex Placebo (GA-0034)
    Number of subjects analysed
    199
    198
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    0.1 ± 22.2
    1.8 ± 23.6
    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 Placebo (GA-0034)
    Number of subjects analysed
    172
    178
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.6 ± 2.9
    -0.3 ± 2.8
    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
    Reporting group description
    The Safety Population included all participants receiving at least 1 dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    The Safety Population included all patients 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.

    Serious adverse events
    Sativex Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 199 (23.62%)
    43 / 198 (21.72%)
         number of deaths (all causes)
    27
    27
         number of deaths resulting from adverse events
    27
    27
    Vascular disorders
    Deep vein thrombosis
         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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 199 (1.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         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
    Neoplasm progression
         subjects affected / exposed
    31 / 199 (15.58%)
    28 / 198 (14.14%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 28
         deaths causally related to treatment / all
    0 / 25
    0 / 24
    Tumour 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
    General disorders and administration site conditions
    Device occlusion
         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
    Completed suicide
         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
    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
    Hallucination, visual
         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
    Mental status changes
         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
    Injury, poisoning and procedural complications
    Fall
         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
    Atrial fibrillation
         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
    Cardiac failure congestive
         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
    Blood and lymphatic system disorders
    Neutropenia
         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
    Pancytopenia
         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
    Thrombocytopenia
         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
    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
    Pulmonary embolism
         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
    Pulmonary toxicity
         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
    Nervous system disorders
    Convulsion
         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
    Spinal cord compression
         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
    Gastrointestinal disorders
    Gastric perforation
         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
    Gastrointestinal 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
    Ileus
         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
    Intestinal obstruction
         subjects affected / exposed
    0 / 199 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         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
    Nausea
         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
    Vomiting
         subjects affected / exposed
    1 / 199 (0.50%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         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
    Musculoskeletal and connective tissue disorders
    Back pain
         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
    Metabolism and nutrition disorders
    Electrolyte imbalance
         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
    Infections and infestations
    Clostridium difficile colitis
         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
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 199 (1.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 199 (0.50%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory 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
    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 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 199 (34.67%)
    53 / 198 (26.77%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 199 (8.04%)
    8 / 198 (4.04%)
         occurrences all number
    16
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 199 (6.03%)
    10 / 198 (5.05%)
         occurrences all number
    12
    10
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 199 (5.53%)
    13 / 198 (6.57%)
         occurrences all number
    11
    14
    Nausea
         subjects affected / exposed
    31 / 199 (15.58%)
    20 / 198 (10.10%)
         occurrences all number
    34
    21
    Vomiting
         subjects affected / exposed
    15 / 199 (7.54%)
    11 / 198 (5.56%)
         occurrences all number
    15
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 199 (7.04%)
    12 / 198 (6.06%)
         occurrences all number
    14
    12

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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 participant population which was one of terminally ill, advanced cancer participants 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 changes in wording to improve clarity. • 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 IR 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. • Various minor administrative changes were made throughout the protocol to aid clarity for the reader. For example, height and weight were mentioned in the synopsis but were not clear in the visit procedures. Also, the amount of blood drawn was corrected to 9 mL, and the Columbia-Suicide Severity Rating Scale assessment was corrected to show the investigator was to complete this. These were not new procedures in the protocol but merely corrections of errors to ensure the protocol accurately reflected the study procedures. References were also updated accordingly and Esoterix was renamed Labcorp Clinical Trials, which was purely to reflect a name change of the company. Additionally, wording was updated regarding additional countries where Sativex was licensed at
    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/28923526
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