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    Clinical Trial Results:
    A multicenter, non-comparative, open-label extension study to assess the long term safety of Sativex oromucosal spray (Sativex®; Nabiximols) as adjunctive therapy in patients with uncontrolled persistent chronic cancer related pain.

    Summary
    EudraCT number
    2009-016529-32
    Trial protocol
    BE   GB   CZ   HU   DE   PL   LT   LV   EE   BG   ES   IT   RO  
    Global end of trial date
    27 Jan 2016

    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
    GWCA0999
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01337089
    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
    20 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of long-term Sativex® (nabiximols) therapy when used as an adjunctive (not breakthrough) measure in participants with advanced cancer.
    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
    19 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 90
    Country: Number of subjects enrolled
    United States: 172
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czech Republic: 51
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Poland: 151
    Country: Number of subjects enrolled
    Romania: 85
    Worldwide total number of subjects
    660
    EEA total number of subjects
    462
    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)
    443
    From 65 to 84 years
    210
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    Participants enrolled in this study included those who had taken part in studies NCT01262651 (GWCA0958), NCT01361607 (GWCA0962), and NCT01424566 (GWCA1103) and who chose to continue treatment by enrolling in this study, as well as new participants who met all inclusion criteria and did not meet any of the exclusion criteria.

    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 Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    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 6 months. 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 6 months. 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
    Sativex
    Started
    660
    Received at Least 1 Dose of Study Drug
    660
    Safety Population
    660
    Efficacy Dataset
    659
    Completed
    256
    Not completed
    404
         Met withdrawal criteria
    3
         Physician decision
    33
         Adverse event
    237
         Consent withdrawn by subject
    129
         Lost to follow-up
    2

    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 6 months. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).

    Reporting group values
    Sativex Total
    Number of subjects
    660 660
    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)
    443 443
        From 65-84 years
    210 210
        85 years and over
    7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.2 ± 11.1 -
    Gender categorical
    Units: Subjects
        Female
    313 313
        Male
    347 347

    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 6 months. Each 100 μL actuation delivered 2.7 milligrams (mg) delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD).

    Subject analysis set title
    Sativex (Safety Population)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Population included all participants receiving at least 1 dose of study drug.

    Primary: Percent Of Participants With Treatment-emergent Adverse Events

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    End point title
    Percent Of Participants With Treatment-emergent Adverse Events [1]
    End point description
    Treatment-emergent Adverse Events (TEAEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 17.0. A TEAE is defined as an adverse event with an onset after the start of study drug treatment. The percent of participants who experienced one or more TEAEs is reported.
    End point type
    Primary
    End point timeframe
    Baseline, Day 183
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses were not performed for this open-label extension study.
    End point values
    Sativex (Safety Population)
    Number of subjects analysed
    660
    Units: percent of participants
        number (not applicable)
    82.9
    No statistical analyses for this end point

    Secondary: Change From Baseline In Mean NRS Average Pain During The Last Period

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    End point title
    Change From Baseline In Mean NRS Average Pain During The Last Period
    End point description
    Participants indicated the level of pain experienced in the last 24 hours on an 11-point Numerical Rating Scale (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: Last Period 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, Last Period (Days 156-183) or last 27 days of treatment
    End point values
    Sativex (Safety Population)
    Number of subjects analysed
    634
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.0 ± 1.8
    No statistical analyses for this end point

    Secondary: Change From Baseline In Mean Sleep Disruption NRS During The Last Period

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    End point title
    Change From Baseline In Mean Sleep Disruption NRS During The Last Period
    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: Last Period 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, Last Period (Days 156-183) or last 27 days of treatment
    End point values
    Sativex (Safety Population)
    Number of subjects analysed
    634
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.1 ± 1.9
    No statistical analyses for this end point

    Secondary: Patient Satisfaction Questionnaire At Last Visit (Up To Day 183)

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    End point title
    Patient Satisfaction Questionnaire At Last Visit (Up To Day 183)
    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.
    End point type
    Secondary
    End point timeframe
    Last Visit (up to Day 183)
    End point values
    Sativex (Safety Population)
    Number of subjects analysed
    618
    Units: participants
        Extremely Satisfied
    56
        Very Satisfied
    230
        Slightly Satisfied
    185
        Neutral
    82
        Slightly Dissatisfied
    33
        Very Dissatisfied
    22
        Extremely Dissatisfied
    10
    No statistical analyses for this end point

    Secondary: Change From Baseline In NRS Constipation At Last Visit (Up To Day 183)

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    End point title
    Change From Baseline In NRS Constipation At Last Visit (Up To Day 183)
    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 - 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 183)
    End point values
    Sativex (Safety Population)
    Number of subjects analysed
    619
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.1 ± 2.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 197 post-enrollment
    Adverse event reporting additional description
    The Safety Population included all participants receiving at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sativex (Safety Population)
    Reporting group description
    The Safety Population included all participants receiving at least 1 dose of study drug.

    Serious adverse events
    Sativex (Safety Population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    301 / 660 (45.61%)
         number of deaths (all causes)
    190
         number of deaths resulting from adverse events
    190
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inferior vena caval occlusion
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Venous thrombosis limb
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cancer pain
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    209 / 660 (31.67%)
         occurrences causally related to treatment / all
    0 / 214
         deaths causally related to treatment / all
    0 / 179
    Ovarian cancer
         subjects affected / exposed [1]
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Local swelling
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    6 / 660 (0.91%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Depression
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Genital haemorrhage
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal fistula
         subjects affected / exposed [2]
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    5 / 660 (0.76%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural headache
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stoma complication
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 660 (0.76%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 660 (1.21%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Convulsion
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    6 / 660 (0.91%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tongue haemorrhage
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 660 (1.06%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    5 / 660 (0.76%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dry gangrene
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 660 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 660 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 660 (0.91%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 660 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subacute endocarditis
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 660 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event affects only female participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event affects only female participants.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sativex (Safety Population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    291 / 660 (44.09%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    41 / 660 (6.21%)
         occurrences all number
    46
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    37 / 660 (5.61%)
         occurrences all number
    40
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    39 / 660 (5.91%)
         occurrences all number
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    51 / 660 (7.73%)
         occurrences all number
    55
    Somnolence
         subjects affected / exposed
    38 / 660 (5.76%)
         occurrences all number
    43
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    50 / 660 (7.58%)
         occurrences all number
    51
    Fatigue
         subjects affected / exposed
    35 / 660 (5.30%)
         occurrences all number
    44
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    44 / 660 (6.67%)
         occurrences all number
    44
    Diarrhoea
         subjects affected / exposed
    41 / 660 (6.21%)
         occurrences all number
    46
    Nausea
         subjects affected / exposed
    86 / 660 (13.03%)
         occurrences all number
    96
    Vomiting
         subjects affected / exposed
    59 / 660 (8.94%)
         occurrences all number
    71
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    49 / 660 (7.42%)
         occurrences all number
    54

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2010
    Alignment with the parent study protocols following amendments in response to a United States (US) Food and Drug Administration (FDA) end of phase 2 meeting and the results of the phase 2b dose-ranging study, including changes to the target dose range, titration schedule, study questionnaires, follow-up period, terminology and general clarifications, and administrative and safety updates.
    16 Jul 2012
    * Section 11.7 was updated following FDA 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.
    14 Mar 2013
    An annex to the protocol (Annex 1) 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 US and United Kingdom (UK) centers from the point of implementation onwards.
    09 Apr 2013
    Two annexes to the protocol (Annex 2 [UK only] and Annex 3 [US only]) evaluated a new child-resistant, senior-friendly dispenser with integrated dose counter.
    14 Jul 2014
    An annex to the protocol (Annex 4) allowed participants in the UK to enter this study and use the dispenser with integrated dose counter without first having participated in a parent study.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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