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    Clinical Trial Results:
    A two-part, placebo-controlled, study of the safety and efficacy of Sativex oromucosal spray (Sativex®; Nabiximols) as adjunctive therapy in relieving uncontrolled persistent chronic pain in patients with advanced cancer, who have inadequate analgesia even with optimized chronic opioid therapy

    Summary
    EudraCT number
    		 2010-022905-17
    Trial protocol
    		 ES   IT   GB   LT   PL   DE   HU   RO   BG  
    Global end of trial date
    28 Dec 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
    GWCA1103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01424566
    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
    Switchboard, GW Pharmaceuticals Ltd., GW Pharmaceuticals Ltd., +44 1980557000, medinfo@gwpharm.com
    Scientific contact
    Switchboard, GW Pharmaceuticals Ltd., 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
    23 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Sativex® (nabiximols), compared with placebo, when used as an adjunctive measure, in relieving uncontrolled persistent chronic pain (not breakthrough pain) in participants with advanced cancer, who had inadequate analgesia even with 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
    29 Jun 2012
    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
    Poland: 149
    Country: Number of subjects enrolled
    Romania: 66
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Lithuania: 17
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Israel: 49
    Country: Number of subjects enrolled
    Taiwan: 18
    Worldwide total number of subjects
    406
    EEA total number of subjects
    328
    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)
    259
    From 65 to 84 years
    141
    85 years and over
    6

    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 entered the single-blind treatment period but did not administer any study drug.

    Period 1
    Period 1 title
    Single-blind Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Single-blind 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 2 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 2 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.

    Number of subjects in period 1
    		Single-blind Sativex
    Started
    406
    Received at least 1 dose of study drug
    404
    Single-blind Safety Population
    404
    Met double-blind randomization criteria
    206
    Completed
    206
    Not completed
    200
         Consent withdrawn by subject
    16
         Physician decision
    2
         Did not meet inclusion criteria
    108
         Did not administer any study drug
    2
         Adverse event
    71
         Met exclusion criteria
    1
    Period 2
    Period 2 title
    Double-blind Treatment
    Is this the baseline period?
    		 No
    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 (IVRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-blind Sativex
    Arm description
    		 Sativex was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in Numerical Rating Scale (NRS) pain scores during the single-blind treatment period (Part A).
    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 for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. 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
    		 Double-blind Placebo (GA-0034)
    Arm description
    		 Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).
    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 for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings.

    Number of subjects in period 2
    		Double-blind Sativex Double-blind Placebo (GA-0034)
    Started
    103
    103
    Received at least 1 dose of study drug
    103
    103
    Randomized Safety Population
    103
    103
    Intent to Treat (ITT) Population
    103
    103
    Completed
    78
    88
    Not completed
    25
    15
         Consent withdrawn by subject
    2
    -
         Physician decision
    1
    1
         Adverse event
    21
    13
         Lack of efficacy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Single-blind 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 2 weeks. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).

    Reporting group values
    		 Single-blind Sativex Total
    Number of subjects
    		 406 406
    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)
    		 259 259
        From 65-84 years
    		 141 141
        85 years and over
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    		 177 177
        Male
    		 229 229

    End points

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    End points reporting groups
    Reporting group title
    Single-blind 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 2 weeks. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).
    Reporting group title
    Double-blind Sativex
    Reporting group description
    		 Sativex was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in Numerical Rating Scale (NRS) pain scores during the single-blind treatment period (Part A).

    Reporting group title
    Double-blind Placebo (GA-0034)
    Reporting group description
    		 Placebo was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, for 5 weeks, at the same level of dosing attained during the last 4 days of the single-blind period; however, the number of sprays could be decreased based upon tolerability throughout the study. Placebo oromucosal spray contained ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring and colorings. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).

    Subject analysis set title
    Single-blind 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.

    Subject analysis set title
    Double-blind 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.

    Subject analysis set title
    Double-blind 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.

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline NRS average pain score. The participant's Randomization (Part B) baseline pain 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in average pain score from Randomization (Part B) Baseline.
    End point type
    Primary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.5 ± 1.3
    0.5 ± 1.6
    Statistical analysis title
    		 Change From Baseline In Mean NRS Average Pain
    Comparison groups
    Double-blind Sativex (ITT Population) v Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9173
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.38

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

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    End point title
    		 Percent Improvement From Eligibility 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 NRS, where a score of 0 was “no pain” and 10 was “pain as bad as you can imagine”. Eligibility Baseline = mean score from the 3-day eligibility period. End of Treatment = mean score over last (up to) 4 days to the final pain score at End of Treatment or up until Day 36 of the double-blind period, whichever is earlier, or final score available (prematurely terminated). Percentage improvement from baseline (Imp%) was calculated as: Imp% = (Eligibility Baseline pain NRS mean - End of Treatment pain NRS mean)/Eligibility 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, 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
    Secondary
    End point timeframe
    Eligibility Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: percent improvement
        median (inter-quartile range (Q1-Q3))
    33.3 (18.2 to 51.8)
    35.7 (18.8 to 51.3)
    No statistical analyses for this end point

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline NRS worst pain score. The participant's Randomization (Part B) baseline worst pain 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in worst pain score from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.2 ± 1.4
    0.5 ± 1.6
    No statistical analyses for this end point

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline sleep disruption NRS score. The participant's Randomization (Part B) baseline sleep disruption 0-10 NRS value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates an improvement in sleep disruption score from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.2 ± 1.3
    0.5 ± 1.4
    No statistical analyses for this end point

    Secondary: Subject Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period)

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    End point title
    		 Subject Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period)
    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 of the double-blind period or the day 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 of the double-blind period.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    88
    97
    Units: participants
        Very Much Improved
    6
    6
        Much Improved
    28
    35
        Slightly Improved
    35
    26
        No Change
    8
    15
        Slightly Worse
    8
    8
        Much Worse
    3
    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 Of The Double-blind Period)

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    End point title
    		 Physician Global Impression Of Change At Last Visit (Up To Day 36 Of The Double-blind Period)
    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 of the double-blind period.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    90
    97
    Units: participants
        Very Much Improved
    7
    7
        Much Improved
    22
    30
        Slightly Improved
    37
    25
        No Change
    11
    20
        Slightly Worse
    4
    12
        Much Worse
    8
    3
        Very Much Worse
    1
    0
    No statistical analyses for this end point

    Secondary: Patient Satisfaction Questionnaire At Last Visit (Up To Day 36 Of The Double-blind Period)

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    End point title
    		 Patient Satisfaction Questionnaire At Last Visit (Up To Day 36 Of The Double-blind Period)
    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 of the double-blind period.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    89
    97
    Units: participants
        Extremely Satisfied
    5
    5
        Very Satisfied
    30
    38
        Slightly Satisfied
    35
    28
        Neutral
    14
    10
        Slightly Dissatisfied
    2
    11
        Very Dissatisfied
    0
    4
        Extremely Dissatisfied
    3
    1
    No statistical analyses for this end point

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline daily total opioid use. The participant's Randomization (Part B) baseline daily total opioid use value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in use from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    9.0 ± 45.6
    15.5 ± 75.9
    No statistical analyses for this end point

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline daily maintenance opioid dose. The participant's Randomization (Part B) baseline daily maintenance opioid dose value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in dose from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    0.0 ± 11.0
    8.5 ± 54.6
    No statistical analyses for this end point

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

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    End point title
    		 Change From Randomization 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 - Randomization (Part B) Baseline daily maintenance opioid dose. The participant's Randomization (Part B) baseline daily break-through opioid dose value was the mean over the last 4 consecutive days of the single-blind treatment period (Part A; pre-randomization). A negative value indicates a decrease in dose from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, End of Treatment (Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    103
    103
    Units: mg (morphine equivalent)
        arithmetic mean (standard deviation)
    9.0 ± 50.7
    7.0 ± 36.1
    No statistical analyses for this end point

    Secondary: Change From Randomization Baseline In NRS Constipation At Last Visit

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    End point title
    		 Change From Randomization Baseline In NRS Constipation At Last Visit
    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. Change in NRS constipation score was calculated as: Last Visit NRS constipation score - Randomization (Part B) Baseline NRS constipation score. The participant's Randomization (Part B) baseline constipation NRS value was the last evaluation (including unscheduled visits) in the single-blind treatment period (Part A) prior to the first dose of study drug in the double-blind treatment period (Part B). A negative value indicates improvement in condition from Randomization (Part B) Baseline.
    End point type
    Secondary
    End point timeframe
    Randomization Baseline, Last Visit (up to Day 36 of the double-blind period)
    End point values
    		 Double-blind Sativex (ITT Population) Double-blind Placebo (GA-0034) (ITT Population)
    Number of subjects analysed
    89
    97
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.0 ± 1.8
    -0.2 ± 2.2
    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 of the double-blind period post-randomization
    Adverse event reporting additional description
    The Safety Population included all participants receiving at least 1 dose of study drug. Participants were analyzed according to the treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Single-blind Sativex (Safety Population)
    Reporting group description
    		 The Safety Population included all participants receiving at least 1 dose of study drug. Participants were analyzed according to the treatment received.

    Reporting group title
    Double-blind Sativex (Safety Population)
    Reporting group description
    		 The Safety Population included all participants receiving at least 1 dose of study drug. Participants were analyzed according to the treatment received. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).

    Reporting group title
    Double-blind Placebo (GA-0034) (Safety Population)
    Reporting group description
    		 The Safety Population included all participants receiving at least 1 dose of study drug. Participants were analyzed according to the treatment received. To enter the double-blind treatment period (Part B), participants had to achieve at least a 15% improvement in NRS pain scores during the single-blind treatment period (Part A).

    Serious adverse events
    		 Single-blind Sativex (Safety Population) Double-blind Sativex (Safety Population) Double-blind Placebo (GA-0034) (Safety Population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 404 (19.80%)
    33 / 103 (32.04%)
    16 / 103 (15.53%)
         number of deaths (all causes)
    42
    23
    9
         number of deaths resulting from adverse events
    42
    23
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    41 / 404 (10.15%)
    28 / 103 (27.18%)
    11 / 103 (10.68%)
         occurrences causally related to treatment / all
    0 / 41
    0 / 29
    0 / 11
         deaths causally related to treatment / all
    0 / 35
    0 / 22
    0 / 9
    Tumour haemorrhage
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Breakthrough pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    ECG signs of myocardial ischaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sedation
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 103 (1.94%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 404 (0.74%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Single-blind Sativex (Safety Population) Double-blind Sativex (Safety Population) Double-blind Placebo (GA-0034) (Safety Population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 404 (24.01%)
    21 / 103 (20.39%)
    17 / 103 (16.50%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 404 (0.00%)
    7 / 103 (6.80%)
    4 / 103 (3.88%)
         occurrences all number
    0
    7
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 404 (6.68%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    28
    0
    0
    Somnolence
         subjects affected / exposed
    46 / 404 (11.39%)
    6 / 103 (5.83%)
    1 / 103 (0.97%)
         occurrences all number
    47
    6
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 404 (0.00%)
    5 / 103 (4.85%)
    6 / 103 (5.83%)
         occurrences all number
    0
    5
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 404 (0.00%)
    6 / 103 (5.83%)
    6 / 103 (5.83%)
         occurrences all number
    0
    6
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    25 / 404 (6.19%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    25
    0
    0
    Vomiting
         subjects affected / exposed
    21 / 404 (5.20%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    21
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 404 (0.00%)
    6 / 103 (5.83%)
    3 / 103 (2.91%)
         occurrences all number
    0
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2011
    An administrative error led to the inclusion of blood draw volumes, in relation to laboratory samples, in the protocol synopsis and additionally, the volumes stated were inaccurate. As blood draw volumes were not mentioned anywhere else within the protocol they were removed from the synopsis.
    06 Dec 2011
    An annex to the protocol (Annex 1) was issued to allow the collection of relevant dose-concentration relationship information in participants who were representative of the target population treated with Sativex.
    13 Apr 2012
    This amendment to Protocol Annex 1 provided clarification of the participant population by detailing the different racial groups to be recruited into the pharmacokinetic (PK) annex.
    15 Nov 2012
    * Wording was amended to make it clearer for the reader with regards to the criteria for changes to opioid medications during the eligibility period. * Wording in Sections 8.2.1, 8.2.2, and 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 was updated to clarify to investigators that it was acceptable to unblind prior to contacting GW Pharmaceuticals Ltd., but where possible, GW Pharmaceuticals Ltd. encouraged communication first. * Updates were made to clarify that, for this study, the electronic data capture could not be used to amend a participant’s ‘status’ (for example, screen fail/randomize/complete/withdrawn) within the study, or to resupply drug. These processes could only be carried out by the IVRS. * The wording in Section 9.1.8 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. However, there were no additional requirements of either the center or participant if this confirmatory test was performed. * Further text was added to both the protocol and protocol synopsis to clarify what was required of the participant, with regards to study drug dosing and continued use of the IVRS, at Day 22 of the double-blind period. * Following Food and Drug Administration guidance, the protocol was updated to clarify that GW Pharmaceuticals Ltd. may have needed to follow-up with the study 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 (Annex 2) described the methodology for identifying and evaluating clinical trial adverse event data through systematic categorization, tabulation, and analysis which can illuminate an abuse potential signal. This impacted study procedures for United States (US) and United Kingdom centers from the point of implementation onwards.
    16 Apr 2013
    An annex to the protocol (Annex 3) described the methodology for the assessment of potential physical dependence and withdrawal effects by use of the Cannabis Withdrawal Scale in participants who withdrew from study drug at any point. It also allowed for the inclusion of the Health Service Utilization Questionnaire to assess participant contact with health care services.
    04 Jul 2014
    * This amendment to Protocol Annex 1 allowed Caucasian participants to be recruited from centers in the Europe and Israel as well as the US. The number of Caucasian participants to be recruited was also increased from 40 to 50 (with a related increase in overall Annex participants from 130 to 140). * Addition of PK parameters to include 6-hydroxy-(OH)-CBD and 7-OH-CBD as well as other THC and CBD minor metabolites, should validated tests have existed at the time of analysis. * There were amendments to the text to clarify that the single-blind period study drug only was to be used during Annex 1 and that its single-blind status was to be maintained.
    19 Jan 2015
    This amendment to Protocol Annex 1 included a change to the participant numbers and the countries involved as well as providing further clarification regarding the aims of the annex such as, exploring the potential PK differences between Asian and Caucasian racial groups.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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