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    Clinical Trial Results:
    Tetra-hydro-cannabinol, cannabidiol and their combination for the treatment of peripheral neuropathic pain. A randomised placebo-controlled trial.

    Summary
    EudraCT number
    		 2017-005198-38
    Trial protocol
    		 DK  
    Global end of trial date
    03 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2022
    First version publication date
    12 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CANNA1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    J. B. Winsløws Vej 4, Odense, Denmark,
    Public contact
    Neuromuscular team, Odense University Hospital, 0045 65412471, soeren.sindrup@rsyd.dk
    Scientific contact
    Neuromuscular team, Odense University Hospital, 0045 65412471, soeren.sindrup@rsyd.dk
    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
    01 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to test if the primary active components of cannabis (tetra-hydro-cannabinol and cannabidiol) provide a clinically relevant pain relief in peripheral neuropathic pain.
    Protection of trial subjects
    Escape medication could be used and patients could continue some usual neuropathic pain treatments (gabapentin/pregabalin/antidepressants)
    Background therapy
    		 Placebo
    Evidence for comparator
    		 None
    Actual start date of recruitment
    02 Apr 2018
    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
    Denmark: 145
    Worldwide total number of subjects
    145
    EEA total number of subjects
    145
    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)
    74
    From 65 to 84 years
    70
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited in Denmark during the period December 2018 to May 2021.

    Pre-assignment
    Screening details
    		 The patients were recruited from out-patient clinics, adds in local media, and through social media. 169 patients were sreened for participation and 145 patients entered the study. 115 patients were randomised for treatment and the main reason to not being randomised were low pain score, withdrawn consent, and co-morbidities.

    Pre-assignment period milestones
    Number of subjects started
    		 145
    Number of subjects completed
    		 115

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 8
    Reason: Number of subjects
    		 Physician decision: 3
    Reason: Number of subjects
    		 Protocol deviation: 2
    Reason: Number of subjects
    		 driving ban: 1
    Reason: Number of subjects
    		 alcohol consumption: 2
    Reason: Number of subjects
    		 co-morbidities: 5
    Reason: Number of subjects
    		 low pain score: 2
    Reason: Number of subjects
    		 unknown: 7
    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
    Blinding implementation details
    Allocation to treatment via computer generated list. Study medication of identical appearance and smell.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cannabidiol
    Arm description
    		 Treatment with cannabidiol flexible dose from 5 mg to 50 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cannabidiol
    Investigational medicinal product code
    Other name
    CBD
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing twice daily. Starting dose 5 mg/day and maximum dose 50 mg/day.

    Arm title
    		 Tetra-hydro-cannabinol
    Arm description
    		 Treatment with flexible dose of tetra-hydro-cannabinol from 2.5 mg/day to 25 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tetra-hydro-cannabinol
    Investigational medicinal product code
    Other name
    THC
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed twice daily and dosage from 2.5 mg/day to 25 mg/day

    Arm title
    		 Combination
    Arm description
    		 Flexible dosing of combination of cannabidiol and tetra-hydro-cannabinol dosage 5 mg/2.5 mg to 50 mg/25 mg daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cannabidiol plus tetra-hydro-cannabinol
    Investigational medicinal product code
    Other name
    CBD/THC
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed twice daily. Dosage from CBD 5 mg/day and THC 2.5 mg/day to CBD 50 mg/day and THC 25 mg/day

    Arm title
    		 Placebo
    Arm description
    		 Placebo treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    PLA
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosedtwiced daily. Dose from 1 capsule daily to 10 capsules daily.

    Number of subjects in period 1 [1]
    		Cannabidiol Tetra-hydro-cannabinol Combination Placebo
    Started
    27
    28
    30
    30
    Completed
    23
    24
    24
    25
    Not completed
    4
    4
    6
    5
         unknown
    1
    -
    1
    1
         co-morbidities
    -
    -
    -
    3
         Adverse event, non-fatal
    2
    1
    4
    -
         co-morbidity
    -
    2
    -
    -
         hospitalization
    -
    1
    1
    -
         Lack of efficacy
    1
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 145 subjects entered the pre-assignment period and 115 entered the period1 including the baseline and treatment periods.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cannabidiol
    Reporting group description
    		 Treatment with cannabidiol flexible dose from 5 mg to 50 mg

    Reporting group title
    Tetra-hydro-cannabinol
    Reporting group description
    		 Treatment with flexible dose of tetra-hydro-cannabinol from 2.5 mg/day to 25 mg/day.

    Reporting group title
    Combination
    Reporting group description
    		 Flexible dosing of combination of cannabidiol and tetra-hydro-cannabinol dosage 5 mg/2.5 mg to 50 mg/25 mg daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Reporting group values
    		 Cannabidiol Tetra-hydro-cannabinol Combination Placebo Total
    Number of subjects
    		 27 28 30 30 115
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age in years
    Units: years
        median (full range (min-max))
    		 64 (43 to 79) 62 (27 to 83) 68 (22 to 95) 66 (39 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13 21 17 64
        Male
    		 14 15 9 13 51
    Subject analysis sets

    Subject analysis set title
    Intention -to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects being randomised and starting treatment.

    Subject analysis sets values
    		 Intention -to-treat
    Number of subjects
    115
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age in years
    Units: years
        median (full range (min-max))
    65 (22 to 95)
    Gender categorical
    Units: Subjects
        Female
    64
        Male
    51

    End points

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    End points reporting groups
    Reporting group title
    Cannabidiol
    Reporting group description
    		 Treatment with cannabidiol flexible dose from 5 mg to 50 mg

    Reporting group title
    Tetra-hydro-cannabinol
    Reporting group description
    		 Treatment with flexible dose of tetra-hydro-cannabinol from 2.5 mg/day to 25 mg/day.

    Reporting group title
    Combination
    Reporting group description
    		 Flexible dosing of combination of cannabidiol and tetra-hydro-cannabinol dosage 5 mg/2.5 mg to 50 mg/25 mg daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment

    Subject analysis set title
    Intention -to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects being randomised and starting treatment.

    Primary: Change in average weekly pain NRS score

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    End point title
    		 Change in average weekly pain NRS score
    End point description
    Averega daily pain was scored daily and recorded and an average weekly scores was calculated. From these average weekly pain scores changes from the baseline week to each of the treatment weeks were calculated. In results table only change from baseline to week 8 given.
    End point type
    Primary
    End point timeframe
    The change in pain score (average weekly score) from baseline to each of the treatment weeks 1 to 8 were used.
    End point values
    		 Cannabidiol Tetra-hydro-cannabinol Combination Placebo Intention -to-treat
    Number of subjects analysed
    27
    28
    30
    30
    115
    Units: NRS points 0-10
        arithmetic mean (standard deviation)
    -0.58 ± 1.74
    -1.43 ± 2.09
    -1.93 ± 1.90
    -1.86 ± 2.22
    -1.47 ± 2.04
    Statistical analysis title
    		 General linear model on change in pain scores
    Statistical analysis description
    General linear model with changes in pain scores from baseline to each treatment week (1 trough 8) for each treatment (CBD; THC CBD/THC) compared to placebo.
    Comparison groups
    Cannabidiol v Tetra-hydro-cannabinol v Combination v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.02 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Analysis model taking all treatment weeks into account.
    [2] - 0.05 significance level corrected for multiple comparisons to 0.02 (0.05/3). In GLM with all treatment weeks: Placebo vs Cannabidiol: 0.04 Placebo vs Tetra-hydro-cannabinol: 0.41 Placebo vs Combination Cannabidiol and tetra-hydro-cannabinol: 0.60

    Secondary: 30% pain relief

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    End point title
    		 30% pain relief
    End point description
    Number of patients that at the end of week 8 had had a reduction in pain score from baseline of 30% or more.
    End point type
    Secondary
    End point timeframe
    Baseline to week 8 of treatment.
    End point values
    		 Cannabidiol Tetra-hydro-cannabinol Combination Placebo Intention -to-treat
    Number of subjects analysed
    27
    28
    30
    30
    115
    Units: subjects
        Response
    9
    12
    18
    17
    56
        Non-response
    18
    16
    12
    13
    59
    Statistical analysis title
    		 Comparison of proportions
    Statistical analysis description
    Comparison of each of the treatment arms with the placebo arm
    Comparison groups
    Cannabidiol v Tetra-hydro-cannabinol v Combination v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.02 [3]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - Usual significance level 0.05 corrected for multiple comparisons to 0.02 (0.05/3)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events reported as "present" during baseline and treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group title
    Cannabidiol
    Reporting group description
    		 -

    Reporting group title
    Tetra-hydro-cannabidiol
    Reporting group description
    		 -

    Reporting group title
    Combination
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Baseline Cannabidiol Tetra-hydro-cannabidiol Combination Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Baseline Cannabidiol Tetra-hydro-cannabidiol Combination Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 114 (99.12%)
    16 / 24 (66.67%)
    22 / 26 (84.62%)
    23 / 27 (85.19%)
    17 / 25 (68.00%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Nervous system disorders
    Dry mouth
         subjects affected / exposed
    28 / 114 (24.56%)
    7 / 24 (29.17%)
    8 / 26 (30.77%)
    9 / 27 (33.33%)
    7 / 25 (28.00%)
         occurrences all number
    28
    7
    8
    9
    7
    Headache
         subjects affected / exposed
    13 / 114 (11.40%)
    2 / 24 (8.33%)
    3 / 26 (11.54%)
    4 / 27 (14.81%)
    0 / 25 (0.00%)
         occurrences all number
    13
    2
    3
    4
    0
    Nightmare
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    12 / 114 (10.53%)
    1 / 24 (4.17%)
    3 / 26 (11.54%)
    2 / 27 (7.41%)
    3 / 25 (12.00%)
         occurrences all number
    12
    1
    3
    2
    3
    Drowsiness
         subjects affected / exposed
    29 / 114 (25.44%)
    2 / 24 (8.33%)
    6 / 26 (23.08%)
    8 / 27 (29.63%)
    5 / 25 (20.00%)
         occurrences all number
    29
    2
    6
    8
    5
    Facial flush
         subjects affected / exposed
    8 / 114 (7.02%)
    1 / 24 (4.17%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    8
    1
    2
    0
    2
    Blurred vision
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    6
    0
    0
    1
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    10 / 114 (8.77%)
    1 / 24 (4.17%)
    3 / 26 (11.54%)
    2 / 27 (7.41%)
    2 / 25 (8.00%)
         occurrences all number
    10
    1
    3
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    Diarrhoea
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    1
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervousness
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle pain
         subjects affected / exposed
    30 / 114 (26.32%)
    8 / 24 (33.33%)
    6 / 26 (23.08%)
    1 / 27 (3.70%)
    3 / 25 (12.00%)
         occurrences all number
    30
    8
    6
    1
    3

    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? No

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