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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, 2-way Crossover Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Patients with Multiple Sclerosis

    Summary
    EudraCT number
    		 2019-002625-29
    Trial protocol
    		 PL   GB   CZ  
    Global end of trial date
    10 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2023
    First version publication date
    12 May 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GWSP19066
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04657666
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GW Pharma Ltd
    Sponsor organisation address
    Sovereign House, Vision Park, Histon, Cambridge, United Kingdom,
    Public contact
    Clinical Trial Disclosure & Transparency, GW Pharma Limited, +1 215-832-3750, ClinicalTrialDisclosure@JazzPharma.com
    Scientific contact
    Clinical Trial Disclosure & Transparency, GW Pharma Limited, +1 215-832-3750, ClinicalTrialDisclosure@JazzPharma.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
    10 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-6; LLMT) in patients with MS who have not achieved adequate relief from spasticity with other antispasticity medications
    Protection of trial subjects
    This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki, the ICH Tripartite Guideline for GCP Topic E6(R2), the EU Clinical Trials Directive, the EU GCP Directive, and the clinical study regulations adopting European Commission Directives into national legislation. The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents were submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before the study was initiated.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2020
    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
    Poland: 67
    Country: Number of subjects enrolled
    Czechia: 1
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    66
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 68 participants who met all inclusion and no exclusion criteria were randomized to treatment at 9 clinic centers in Poland and 1 center in Czech Republic.

    Pre-assignment
    Screening details
    		 Randomized participants completed two 21-day treatment periods. A washout period (7 days) separated the 2 treatment periods. During the washout period, participants continued their current MS anti-spasticity medications. Each treatment period included a dose titration phase (~14 days) and maintenance-dose phase (~7 days) at optimized dose level.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nabiximols
    Arm description
    		 Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nabiximols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered GW-1000-02 (nabiximols) as an oromucosal spray for 21 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered placebo as an oromucosal spray for 21 days

    Arm title
    		 Placebo
    Arm description
    		 Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 31; Treatment Period 2).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered placebo as an oromucosal spray for 21 days

    Investigational medicinal product name
    Nabiximols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered GW-1000-02 (nabiximols) as an oromucosal spray for 21 days

    Number of subjects in period 1
    		Nabiximols Placebo
    Started
    33
    35
    Completed
    30
    33
    Not completed
    3
    2
         Adverse event, non-fatal
    1
    -
         Decision by investigator, GW, or authority
    -
    1
         Withdrawal of participant consent
    2
    1
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 31; Treatment Period 2).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered placebo as an oromucosal spray for 21 days

    Investigational medicinal product name
    Nabiximols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered GW-1000-02 (nabiximols) as an oromucosal spray for 21 days

    Arm title
    		 Nabiximols
    Arm description
    		 Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nabiximols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered GW-1000-02 (nabiximols) as an oromucosal spray for 21 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal spray
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Patients self-administered placebo as an oromucosal spray for 21 days

    Number of subjects in period 2
    		Placebo Nabiximols
    Started
    33
    30
    Completed
    30
    28
    Not completed
    3
    2
         Adverse event, non-fatal
    3
    -
         Not specified
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nabiximols
    Reporting group description
    		 Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 31; Treatment Period 2).

    Reporting group values
    		 Nabiximols Placebo Total
    Number of subjects
    		 33 35 68
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 31 35 66
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.7 ( 9.9 ) 49.7 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 24 43
        Male
    		 14 11 25

    End points

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    End points reporting groups
    Reporting group title
    Nabiximols
    Reporting group description
    		 Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 31; Treatment Period 2).
    Reporting group title
    Placebo
    Reporting group description
    		 Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 31; Treatment Period 2).

    Reporting group title
    Nabiximols
    Reporting group description
    		 Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).

    Subject analysis set title
    Nabiximols
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combined analysis of patients treated with nabiximols in both Treatment Period 1 and Treatment Period 2.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combined analysis of patients treated with placebo in both Treatment Period 1 and Treatment Period 2.

    Primary: Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)

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    End point title
    		 Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)
    End point description
    LLMT-6 is defined as the average of the 6 individual Modified Ashworth Scale (MAS) transformed scores of knee flexors, knee extensors, and plantar flexors on both sides of the body. Transformed MAS ranges from 0 (no increase in muscle tone) to 5 (affected part rigid in flexion or extension). The combined (treatment period 1 and treatment period 2) least square mean change from baseline in LLMT-6 score is being reported. Negative values indicate an improvement in muscle tone.
    End point type
    Primary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    68
    68
    Units: units on a scale
    least squares mean (standard error)
        Change from baseline in LLMT-6
    -0.23 ( 0.07 )
    -0.26 ( 0.07 )
    Statistical analysis title
    		 Nabiximols vs Placebo
    Comparison groups
    Nabiximols v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7152 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Combined least square mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [1] - Pattern mixture model (PMM) control-based imputation, mixed model repeated measures (MMRM)

    Secondary: Change From Baseline in Lower Limb Muscle Tone-4 (LLMT-4)

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    End point title
    		 Change From Baseline in Lower Limb Muscle Tone-4 (LLMT-4)
    End point description
    LLMT-4 is defined as the average of the 4 individual MAS transformed scores of knee flexors and knee extensors on both sides of the body. Transformed MAS ranges from 0 (no increase in muscle tone) to 5 (affected part rigid in flexion or extension). The combined (treatment period 1 and treatment period 2) least square mean change from baseline in LLMT-4 score is being reported. Negative values indicate an improvement in muscle tone.
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    68
    68
    Units: units on a scale
    least squares mean (standard error)
        Change from baseline in LLMT-4
    -0.23 ( 0.08 )
    -0.28 ( 0.08 )
    No statistical analyses for this end point

    Secondary: Number of Patients With Any Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Patients With Any Treatment-Emergent Adverse Events (TEAEs)
    End point description
    A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product.
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    66
    65
    Units: patients
    number (not applicable)
        Any TEAE
    27
    15
    No statistical analyses for this end point

    Secondary: Change From Baseline in Blood Pressure

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    End point title
    		 Change From Baseline in Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    62
    61
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic blood pressure
    -3.7 ( 10.48 )
    -2.7 ( 10.85 )
        Diastolic blood pressure
    -3.6 ( 9.06 )
    -1.7 ( 8.44 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heart Rate

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    End point title
    		 Change From Baseline in Heart Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    62
    61
    Units: beats/minute
    arithmetic mean (standard deviation)
        Heart rate
    -2.9 ( 8.12 )
    2.0 ( 9.68 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weight

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    End point title
    		 Change From Baseline in Weight
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    59
    59
    Units: kg
    arithmetic mean (standard deviation)
        Weight
    0.28 ( 1.73 )
    0.56 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI)

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    End point title
    		 Change From Baseline in Body Mass Index (BMI)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    59
    59
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Body mass index (BMI)
    0.09 ( 0.67 )
    0.19 ( 0.81 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Laboratory Values

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    End point title
    		 Change from Baseline in Clinical Laboratory Values
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: 10^9 per liter
    arithmetic mean (standard deviation)
        Leukocytes (n=61; n=59)
    -0.144 ( 1.57 )
    -0.324 ( 1.08 )
        Neutrophils (n=60; n=59)
    0.015 ( 1.57 )
    -0.316 ( 0.99 )
        Basophils (n=60; n=58)
    -0.001 ( 0.04 )
    0.000 ( 0.03 )
        Eosinophils (n=60; n=58)
    0.010 ( 0.08 )
    0.011 ( 0.08 )
        Lymphocytes (n=60; n=58)
    -0.172 ( 0.33 )
    -0.013 ( 0.31 )
        Monocytes (n=60; n=58)
    -0.003 ( 0.16 )
    -0.009 ( 0.15 )
        Platelets (n=61; n=59)
    1.0 ( 40.58 )
    1.7 ( 35.62 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Erythrocytes

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    End point title
    		 Change From Baseline in Erythrocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: 10^12 per liter
    arithmetic mean (standard deviation)
        Erythrocytes
    -0.101 ( 0.27 )
    -0.017 ( 0.19 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemoglobin

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    End point title
    		 Change From Baseline in Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: g/dL
    arithmetic mean (standard deviation)
        Hemoglobin
    -0.22 ( 0.79 )
    -0.03 ( 0.67 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hematocrit

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    End point title
    		 Change From Baseline in Hematocrit
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: ratio
    arithmetic mean (standard deviation)
        Hematocrit
    -0.006 ( 0.03 )
    -0.001 ( 0.02 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Erythrocyte Mean Corpuscular Volume

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    End point title
    		 Change From Baseline in Erythrocyte Mean Corpuscular Volume
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: fL
    arithmetic mean (standard deviation)
        Erythrocyte Mean Corpuscular Volume
    0.64 ( 3.33 )
    0.17 ( 3.00 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin

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    End point title
    		 Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    61
    59
    Units: pg
    arithmetic mean (standard deviation)
        Erythrocyte Mean Corpuscular Hemoglobin
    0.14 ( 0.97 )
    0.04 ( 0.94 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Electrocardiogram Parameters

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    End point title
    		 Change From Baseline in Electrocardiogram Parameters
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    62
    61
    Units: msec
    arithmetic mean (standard deviation)
        PR interval
    11.4 ( 102.54 )
    -1.7 ( 24.79 )
        QRS duration
    0 ( 13.61 )
    -1.0 ( 9.34 )
        QT interval
    2.4 ( 22.19 )
    -3.2 ( 32.57 )
        QTcB interval
    1.1 ( 56.32 )
    10.1 ( 51.80 )
        QTcF interval
    3.0 ( 55.83 )
    6.9 ( 50.80 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Electrocardiogram Pulse Rate

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    End point title
    		 Change From Baseline in Electrocardiogram Pulse Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    62
    61
    Units: beats/minute
    arithmetic mean (standard deviation)
        Pulse rate
    -6.6 ( 8.76 )
    -2.5 ( 9.87 )
    No statistical analyses for this end point

    Secondary: Number of Patients With Suicidal Ideation or Behavior Based on The Columbia Suicide Severity Rating Scale (CSSRS)

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    End point title
    		 Number of Patients With Suicidal Ideation or Behavior Based on The Columbia Suicide Severity Rating Scale (CSSRS)
    End point description
    The C-SSRS is a short questionnaire that is used to assess suicidal ideation (5 questions) and behavior (5 questions) since last patient visit. The questionnaire is completed by participants answering yes or no to each question.
    End point type
    Secondary
    End point timeframe
    Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
    End point values
    		 Nabiximols Placebo
    Number of subjects analysed
    66
    65
    Units: patients
    number (not applicable)
        Baseline: Ideation, Wish to be dead
    0
    0
        Baseline: Ideation, Non-specific active thoughts
    0
    0
        Baseline: Ideation: Active any method no intent
    0
    0
        Baseline: Ideation, Active intent to act no plan
    0
    0
        Baseline: Ideation, Active specific plan/intent
    0
    0
        Baseline: Behavior, Preparatory acts or behavior
    0
    0
        Baseline: Behavior, Aborted attempt
    0
    0
        Baseline: Behavior, Interrupted attempt
    0
    0
        Baseline: Behavior, Actual attempt (non-fatal)
    0
    0
        Baseline: Behavior, Completed suicide
    0
    0
        Baseline: Ideation or behavior
    0
    0
        Baseline: Self-injurious behavior without intent
    0
    0
        Day 15: Ideation, Wish to be dead
    0
    0
        Day 15: Ideation, Non-specific active thoughts
    0
    0
        Day 15: Ideation, Active any method no intent
    0
    0
        Day 15: Ideation, Active intent to act no plan
    0
    0
        Day 15: Ideation, Active specific plan/intent
    0
    0
        Day 15: Behavior, Preparatory acts or behavior
    0
    0
        Day 15: Behavior, Aborted attempt
    0
    0
        Day 15: Behavior, Interrupted attempt
    0
    0
        Day 15: Behavior, Actual attempt (non-fatal)
    0
    0
        Day 15 Behavior, Completed suicide
    0
    0
        Day 15: Ideation or behavior
    0
    0
        Day 15: Self-injurious behavior without intent
    0
    0
        Day 21: Ideation, Wish to be dead
    0
    0
        Day 21: Ideation, Non-specific active thoughts
    0
    0
        Day 21: Ideation, Active any method no intent
    0
    0
        Day 21: Ideation, Active intent to act no plan
    0
    0
        Day 21: Ideation, Active specific plan/intent
    0
    0
        Day 21: Behavior, Preparatory acts or behavior
    0
    0
        Day 21: Behavior, Aborted attempt
    0
    0
        Day 21: Behavior, Interrupted attempt
    0
    0
        Day 21: Behavior, Actual attempt (non-fatal)
    0
    0
        Day 21: Behavior, Completed suicide
    0
    0
        Day 21: Ideation or behavior
    0
    0
        Day 21: Self-injurious behavior without intent
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentrations for Δ9-tetrahydrocannabinol (THC)

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    End point title
    		 Plasma Concentrations for Δ9-tetrahydrocannabinol (THC)
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. Period 2: Day 31: predose,0-2 and 2-4 hr postdose. Day 45: 0-2 and 2-4 hr postdose. Day 51: predose,0-1, 2-3 hr postdose
    End point values
    		 Nabiximols
    Number of subjects analysed
    60
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1, Predose (n=3)
    1.60 ( 1.21 )
        Day 1, O-2H postdose (n=24)
    0.78 ( 0.77 )
        Day 1, 2-4H postdose (n=49)
    0.91 ( 1.77 )
        Day 15, O-2H postdose (n=59)
    1.13 ( 1.20 )
        Day 15, 2-4H postdose (n=59)
    2.07 ( 1.96 )
        Day 21, Predose (n=59)
    0.86 ( 0.66 )
        Day 21, O-2H postdose (n=58)
    1.50 ( 1.77 )
        Day 21, 2-4H postdose (n=60)
    3.08 ( 2.90 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations for Relevant Metabolites, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11- carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), for Δ9-tetrahydrocannabinol (THC)

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    End point title
    		 Plasma Concentrations for Relevant Metabolites, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11- carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), for Δ9-tetrahydrocannabinol (THC)
    End point description
    Plasma concentrations were assessed using blood samples collected at the timepoints specified.
    End point type
    Secondary
    End point timeframe
    Period 1:Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. Period 2:Day 31: predose,0-2 and 2-4 hr postdose. Day 45: 0-2 and 2-4 hr postdose. Day 51: predose,0-1 and 2-3 hr postdose
    End point values
    		 Nabiximols
    Number of subjects analysed
    60
    Units: ng/mL
    arithmetic mean (standard deviation)
        11-OH-THC: Day 1, Predose (n=4)
    1.31 ( 1.87 )
        11-OH-THC: Day 1, O-2H postdose (n=23)
    1.17 ( 1.52 )
        11-OH-THC: Day 1, 2-4H postdose (n=51)
    0.79 ( 1.00 )
        11-OH-THC: Day 15, O-2H postdose (n=58)
    2.12 ( 1.92 )
        11-OH-THC: Day 15, 2-4H postdose (n=58)
    2.91 ( 2.23 )
        11-OH-THC: Day 21, Predose (n=59)
    1.77 ( 1.42 )
        11-OH-THC: Day 21, O-2H postdose (n=58)
    2.22 ( 1.66 )
        11-OH-THC: Day 21, 2-4H postdose (n=59)
    3.75 ( 3.10 )
        11-COOH-THC: Day 1 Predose (n=4)
    19.54 ( 32.94 )
        11-COOH-THC: Day 1, O-2H postdose (n=25)
    10.53 ( 24.16 )
        11-COOH-THC: Day 1, 2-4H postdose (n=51)
    6.49 ( 9.91 )
        11-COOH-THC: Day 15, O-2H postdose (n=59)
    63.75 ( 47.02 )
        11-COOH-THC: Day 15, 2-4H postdose (n=59)
    66.86 ( 45.23 )
        11-COOH-THC: Day 21, Predose (n=60)
    77.59 ( 74.28 )
        11-COOH-THC: Day 21, O-2H postdose (n=60)
    70.53 ( 68.49 )
        11-COOH-THC: Day 21, 2-4H postdose (n=60)
    76.31 ( 59.57 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations for Cannabidiol (CBD)

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    End point title
    		 Plasma Concentrations for Cannabidiol (CBD)
    End point description
    Plasma concentrations were assessed using blood samples collected at the timepoints specified.
    End point type
    Secondary
    End point timeframe
    Period 1:Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. Period 2:Day 31: predose,0-2 and 2-4 hr postdose. Day 45: 0-2 and 2-4 hr postdose. Day 51: predose,0-1 and 2-3 hr postdose
    End point values
    		 Nabiximols
    Number of subjects analysed
    60
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1, Predose (n=4)
    0.24 ( 0.16 )
        Day 1, O-2H postdose (n=21)
    0.46 ( 0.55 )
        Day 1, 2-4H postdose (n=45)
    0.51 ( 0.94 )
        Day 15, O-2H postdose (n=59)
    1.11 ( 0.84 )
        Day 15, 2-4H postdose (n=59)
    1.68 ( 1.29 )
        Day 21, Predose (n=60)
    1.01 ( 0.80 )
        Day 21, O-2H postdose (n=58)
    1.40 ( 1.28 )
        Day 21, 2-4H postdose (n=60)
    2.42 ( 2.17 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations for Relevant Metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and 7-carboxy-cannabidiol (7-COOH-CBD), for Cannabidiol (CBD)

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    End point title
    		 Plasma Concentrations for Relevant Metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and 7-carboxy-cannabidiol (7-COOH-CBD), for Cannabidiol (CBD)
    End point description
    Plasma concentrations were assessed using blood sample collected at the timepoints specified.
    End point type
    Secondary
    End point timeframe
    Period 1:Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. Period 2:Day 31: predose,0-2 and 2-4 hr postdose. Day 45: 0-2 and 2-4 hr postdose. Day 51: predose,0-1 and 2-3 hr postdose
    End point values
    		 Nabiximols
    Number of subjects analysed
    60
    Units: ng/mL
    arithmetic mean (standard deviation)
        7-OH-CBD: Day 1, Predose (n=2)
    0.18 ( 0.07 )
        7-OH-CBD: Day 1, O-2H postdose (n=13)
    0.59 ( 1.00 )
        7-OH-CBD: Day 1, 2-4H postdose (n=34)
    0.27 ( 0.24 )
        7-OH-CBD: Day 15, O-2H postdose (n=59)
    1.14 ( 0.66 )
        7-OH-CBD: Day 15, 2-4H postdose (n=59)
    1.33 ( 0.76 )
        7-OH-CBD: Day 21, Predose (n=60)
    1.15 ( 0.80 )
        7-OH-CBD: Day 21, O-2H postdose (n=58)
    1.22 ( 0.82 )
        7-OH-CBD: Day 21, 2-4H postdose (n=60)
    1.59 ( 0.98 )
        7-COOH-CBD: Day 1, Predose (n=60)
    7.06 ( 4.91 )
        7-COOH-CBD: Day 1, O-2H postdose (n=60)
    15.67 ( 47.41 )
        7-COOH-CBD: Day 1, 2-4H postdose (n=60)
    4.49 ( 3.50 )
        7-COOH-CBD: Day 15, O-2H postdose (n=60)
    76.84 ( 47.81 )
        7-COOH-CBD: Day 15, 2-4H postdose (n=60)
    79.78 ( 46.27 )
        7-COOH-CBD: Day 21, Predose (n=60)
    88.95 ( 69.64 )
        7-COOH-CBD: Day 21, O-2H postdose (n=60)
    78.04 ( 62.73 )
        7-COOH-CBD: Day 21, 2-4H postdose (n=60)
    88.32 ( 62.52 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse event (TEAE) data were collected from baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2).
    Adverse event reporting additional description
    A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Nabiximols
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Nabiximols Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 65 (1.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Facial spasm
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nabiximols Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 66 (28.79%)
    3 / 65 (4.62%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 66 (15.15%)
    1 / 65 (1.54%)
         occurrences all number
    10
    1
    Somnolence
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 66 (7.58%)
    1 / 65 (1.54%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2019
    Clarified the use of a single central safety laboratory, implemented minor edits to the synopsis, and incorporated additional guidance on trial procedures
    11 May 2020
    Primary and secondary endpoints were updated and minor edits regarding trial procedures, statistical considerations, patient eligibility and prohibited therapy, and dose titrations were incorporated
    02 Sep 2021
    Minor updates were made to sections describing trial procedures, patient eligibility and prohibited therapy, statistical considerations, and trial monitoring

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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