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    Clinical Trial Results:
    A phase IIa/b, randomised, double-blind, placebo-controlled, single-site, parallel group clinical trial to examine cannabidiol (CBD) as a pharmacological treatment for cannabis dependence in a young cannabis dependent population.

    Summary
    EudraCT number
    2013-000361-36
    Trial protocol
    GB  
    Global end of trial date
    05 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Jun 2019
    First version publication date
    16 Jun 2019
    Other versions
    Summary report(s)
    EudraCTupload

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0278
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Joint Research Office
    Sponsor organisation address
    1st Floor Maple House (Suite A) 149 Tottenham Court Road, London, United Kingdom, W1T 7DN
    Public contact
    Samim Patel, Joint Research Office, UCL, +44 0207 679 9320 , samim.patel@ucl.ac.uk
    Scientific contact
    Samim Patel, Joint Research Office, UCL, +44 0207 679 9320 , samim.patel@ucl.ac.uk
    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
    09 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    What is the most effective dose of cannabidiol for reducing cannabis use, and is this dose effective as a treatment for cannabis dependence?
    Protection of trial subjects
    The risk of the IMP is minimal and it has been used in humans previously for up to 18 weeks, and with doses of up to 1500mg with no serious side effects. The maximum daily dose and the duration of the trial (800mg for 4 weeks) is the same as a study carried out in a schizophrenic population. All adverse events will be recorded. If the investigator suspects that the subjects’ disease has progressed faster due to the administration of the IMP, then she/he will record and report this as an unexpected adverse event.
    Background therapy
    All subjects (across each of the treatment conditions) are given motivational interviewing to help them stop using cannabis, which can be harmful to their health.
    Evidence for comparator
    CBD has been found to (a) reduce the effects of drug cues - which play a key role in addiction relapse - in cannabis, tobacco and opiate users; (b) offset the harmful effects of THC and brain and behaviour; (c) reduce cigarette smoking.
    Actual start date of recruitment
    31 Mar 2014
    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
    United Kingdom: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    82
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Community based recruitment within the UK

    Pre-assignment
    Screening details
    Screening at telephone interview and screening visit for eligibility

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily oral dose

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily oral dose

    Arm title
    200mg CBD
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral twice daily

    Arm title
    400mg CBD
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral twice daily

    Arm title
    800mg CBD
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral twice daily

    Number of subjects in period 1
    Placebo 200mg CBD 400mg CBD 800mg CBD
    Started
    23
    12
    24
    23
    Completed
    21
    10
    23
    23
    Not completed
    2
    2
    1
    0
         Lost to follow-up
    2
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    200mg CBD
    Reporting group description
    -

    Reporting group title
    400mg CBD
    Reporting group description
    -

    Reporting group title
    800mg CBD
    Reporting group description
    -

    Reporting group values
    Placebo 200mg CBD 400mg CBD 800mg CBD Total
    Number of subjects
    23 12 24 23 82
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    23 12 24 23 82
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.869565 ± 7.436424 27.333333 ± 7.426407 26.583333 ± 6.794606 27.434783 ± 5.829596 -
    Gender categorical
    Units: Subjects
        Female
    6 3 7 7 23
        Male
    17 9 17 16 59

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    200mg CBD
    Reporting group description
    -

    Reporting group title
    400mg CBD
    Reporting group description
    -

    Reporting group title
    800mg CBD
    Reporting group description
    -

    Primary: Lower urinary THC-COOH:creatinine compared to placebo (stage 1)

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    End point title
    Lower urinary THC-COOH:creatinine compared to placebo (stage 1)
    End point description
    Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1. In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 included 200mg CBD, 400mg CBD, 800mg CBD as well as placebo.
    End point type
    Primary
    End point timeframe
    During treatment weeks (1-4)
    End point values
    Placebo 200mg CBD 400mg CBD 800mg CBD
    Number of subjects analysed
    12
    12
    12
    12
    Units: ng/ml
        number (not applicable)
    0
    0
    0
    0
    Statistical analysis title
    Co-primary endpoint 1 (stage 1)
    Statistical analysis description
    In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 included 200mg CBD, 400mg CBD, 800mg CBD as well as placebo Co-primary endpoint 1 (stage 1): lower urinary THC-COOH:creatinine compared to placebo: 200mg CBD P=0.4191; 400mg CBD P=0.9827; 800mg CBD P=0.9488
    Comparison groups
    Placebo v 200mg CBD v 400mg CBD v 800mg CBD
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    > 0.9 [2]
    Method
    Bayesian model
    Confidence interval
    Notes
    [1] - Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1.
    [2] - Co-primary endpoint 1 (stage 1): lower urinary THC-COOH:creatinine compared to placebo: 200mg CBD P=0.4191; 400mg CBD P=0.9827; 800mg CBD P=0.9488

    Primary: More self-reported days abstinent compared to placebo (stage 1)

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    End point title
    More self-reported days abstinent compared to placebo (stage 1)
    End point description
    Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1. In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 included 200mg CBD, 400mg CBD, 800mg CBD as well as placebo.
    End point type
    Primary
    End point timeframe
    During treatment weeks (1-4)
    End point values
    Placebo 200mg CBD 400mg CBD 800mg CBD
    Number of subjects analysed
    12
    12
    12
    12
    Units: Days
        number (not applicable)
    0
    0
    0
    0
    Statistical analysis title
    Co-primary endpoint 2 (stage 1)
    Statistical analysis description
    In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 included 200mg CBD, 400mg CBD, 800mg CBD as well as placebo Co-primary endpoint 2 (stage 1): more self-reported days abstinent compared to placebo: 200mg CBD P=0.0082; 400mg CBD P=0.9354; 800mg CBD P=0.8660
    Comparison groups
    Placebo v 200mg CBD v 400mg CBD v 800mg CBD
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    > 0.9 [4]
    Method
    Bayesian model
    Confidence interval
    Notes
    [3] - Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1.
    [4] - Co-primary endpoint 2 (stage 1): more self-reported days abstinent compared to placebo: 200mg CBD P=0.0082; 400mg CBD P=0.9354; 800mg CBD P=0.8660

    Primary: Lower urinary THC-COOH:creatinine compared to placebo (stage 2)

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    End point title
    Lower urinary THC-COOH:creatinine compared to placebo (stage 2) [5]
    End point description
    Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1. In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 found evidence for ineffectiveness of 200mg CBD, therefore this dose was eliminated and no further randomisation occurred to this dose in stage 2. There was evidence for effectiveness of both 200mg CBD and 400mg CBD compared to placebo. Therefore in stage 2, randomisation continued to the existing groups of placebo, 400mg CBD and 800mg CBD.
    End point type
    Primary
    End point timeframe
    Treatment weeks (1-4)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All endpoints are reported with reference to placebo.
    End point values
    Placebo 400mg CBD 800mg CBD
    Number of subjects analysed
    23
    24
    23
    Units: ng/ml
        number (not applicable)
    0
    0
    0
    Statistical analysis title
    Co-primary endpoint 1 (stage 2)
    Statistical analysis description
    Stage 1 found evidence for ineffectiveness of 200mg CBD, therefore this dose was eliminated and no further randomisation occurred to this dose in stage 2. There was evidence for effectiveness of both 200mg CBD and 400mg CBD compared to placebo. Therefore in stage 2, randomisation continued to the existing groups of placebo, 400mg CBD and 800mg CBD Co-primary endpoint 1 (stage 2): lower urinary THC-COOH:creatinine compared to placebo: 400mg CBD P=0.9995; 800mg CBD P=0.9965
    Comparison groups
    400mg CBD v 800mg CBD v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    > 0.9 [7]
    Method
    Bayesian model
    Confidence interval
    Notes
    [6] - Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1.
    [7] - Co-primary endpoint 1 (stage 2): lower urinary THC-COOH:creatinine compared to placebo: 400mg CBD P=0.9995; 800mg CBD P=0.9965

    Primary: More self-reported days abstinent compared to placebo (stage 2)

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    End point title
    More self-reported days abstinent compared to placebo (stage 2) [8]
    End point description
    Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1. In this adaptive Bayesian trial, randomisation occurred in two stages. Stage 1 found evidence for ineffectiveness of 200mg CBD, therefore this dose was eliminated and no further randomisation occurred to this dose in stage 2. There was evidence for effectiveness of both 200mg CBD and 400mg CBD compared to placebo. Therefore in stage 2, randomisation continued to the existing groups of placebo, 400mg CBD and 800mg CBD.
    End point type
    Primary
    End point timeframe
    Treatment weeks (1-4)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All endpoints are reported with reference to placebo.
    End point values
    Placebo 400mg CBD 800mg CBD
    Number of subjects analysed
    23
    24
    23
    Units: Days
        number (not applicable)
    0
    0
    0
    Statistical analysis title
    Co-primary endpoint 2 (stage 2)
    Statistical analysis description
    Stage 1 found evidence for ineffectiveness of 200mg CBD, therefore this dose was eliminated and no further randomisation occurred to this dose in stage 2. There was evidence for effectiveness of both 200mg CBD and 400mg CBD compared to placebo. Therefore in stage 2, randomisation continued to the existing groups of placebo, 400mg CBD and 800mg CBD Co-primary endpoint 2 (stage 2): more self-reported days abstinent compared to placebo: 400mg CBD P=0.9966; 800mg CBD P=0.9247
    Comparison groups
    Placebo v 400mg CBD v 800mg CBD
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    > 0.9 [10]
    Method
    Bayesian model
    Confidence interval
    Notes
    [9] - Aim: to identify the Most Effective Dose of CBD for reducing cannabis use compared to placebo (MED). A Bayesian model computed the predictive distribution of the outcome, given the evidence available up to that point (weeks 1, 2, 3 and 4). Based on these distributions, for each dose the probability that it is the MED is evidenced by a probability exceeding the pre-specified threshold (Pu) of 0.9; the pre-specified threshold for an ineffective dose (Pl) was 0.1.
    [10] - Co-primary endpoint 2 (stage 2): more self-reported days abstinent compared to placebo: 400mg CBD P=0.9966; 800mg CBD P=0.9247

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to the final follow up (week 24)
    Adverse event reporting additional description
    Total number of adverse events (AEs) reported in each group Placebo (n=23): mild (62), moderate (10), severe (0) 200mg CBD (n=12): mild (40), moderate (4), severe (0) 400mg CBD (n=24): mild (94), moderate (8), severe (0) 800mg CBD (n=23): mild (77), moderate (8), severe (0)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    N/A
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: For reasons of data compatibility the adverse events are reported in the text. Non serious adverse events are listed in this section.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Apr 2017
    After successfully finding evidence for a most effective dose compared to placebo (phase IIa - dose finding trial) the trial was planned to continue into a subsequent trial (phase IIb - efficacy of most effective dose). Due to lack of funding the phase IIb stage was not initiated. The trial was terminated on 30/05/2018 after successful completion of phase IIa.
    -

    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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