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    Clinical Trial Results:
    The effect of bupropion in peripheral neuropathic pain. A randomized, double-blind, placebo-controlled study.

    Summary
    EudraCT number
    		 2019-000243-27
    Trial protocol
    		 DK  
    Global end of trial date
    13 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2025
    First version publication date
    24 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUPROPION2019
    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. Winløwsvej 4, Odense , Denmark, 5000
    Public contact
    Neuromuscular Clinic, Odense University Hospital, 0045 65412471, soeren.sindrup@rsyd.dk
    Scientific contact
    Neuromuscular Clinic, 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
    04 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to determine if bupropion relieves peripheral neuropathic pain
    Protection of trial subjects
    None.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2019
    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: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    140
    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)
    92
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from two counties (Region of Southern Denmark and Region Midt) in Denmark from 3 Sept. 2020 to 13 Oct. 2022. Patients were recruited from the outpatient clinic at the Department of Neurology at Odense University Hospital and Aarhus University, as well as from advertisement on Facebook.

    Pre-assignment
    Screening details
    		 Most important inclusion criteria: Age ≥ 18 years, probable/definite peripheral neuropathic pain for at least 3 months, weekly average of daily pain intensity > 4 (0-10 NRS). Most important exclusion criteria: Other cause of pain, major depression within 6 months, treatment with antidepressants, opioids and drugs with potential interaction.

    Pre-assignment period milestones
    Number of subjects started
    		 140
    Number of subjects completed
    		 123

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 5
    Reason: Number of subjects
    		 Comorbidity: 1
    Reason: Number of subjects
    		 Concomitant medication that could not be withdrawn: 1
    Reason: Number of subjects
    		 Enrolled in another study: 1
    Reason: Number of subjects
    		 Low pain score (NRS < 4): 4
    Reason: Number of subjects
    		 Other cause of pain in same area: 2
    Reason: Number of subjects
    		 Not neuropathic pain: 3
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline to bupropion
    Arm description
    		 Baseline period with no treatment before bupropion
    Arm type
    		 Baseline no treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Arm title
    		 Baseline to placebo
    Arm description
    		 Baseline period with no treatment before placebo
    Arm type
    		 Baseline no treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Baseline to bupropion Baseline to placebo
    Started
    64
    59
    Completed
    64
    59
    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: Patients were excluded before baseline and allocation was started due to the reasons listed in the 'pre-assignment period'-section
    Period 2
    Period 2 title
    Treatment periods summary
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo capsules identical to terbutaline and imipramine capsules. Double-dummy technique. Randomization was done by Sygehus Apotek Fyn using a computer-generated randomization list using block size unknown to the investigators

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bupropion
    Arm description
    		 Treatment with bupropion 150 mg to 300 mg daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bupropion HCl retard
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg once a day for 1 week, followed by 150 mg twice a day for 5 weeks. Age >= 75 years 150 mg a day for 6 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Treatment with placebo capsules
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage (number ogf capsules) corresponding to number of capsules with active substances

    Number of subjects in period 2
    		Bupropion Placebo
    Started
    64
    59
    Completed
    55
    56
    Not completed
    9
    3
         Adverse event, non-fatal
    7
    -
         Too painful
    2
    1
         Lost to follow-up
    -
    2

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 123 123
    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
    Units: years
        arithmetic mean (full range (min-max))
    		 57 (18 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 62 62
        Male
    		 61 61

    End points

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    End points reporting groups
    Reporting group title
    Baseline to bupropion
    Reporting group description
    		 Baseline period with no treatment before bupropion

    Reporting group title
    Baseline to placebo
    Reporting group description
    		 Baseline period with no treatment before placebo
    Reporting group title
    Bupropion
    Reporting group description
    		 Treatment with bupropion 150 mg to 300 mg daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo capsules

    Subject analysis set title
    Intention to treat analysis
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intention to treat analysis set, subjects with data from 1 or 2 treatment periods

    Primary: Numeric Rating of average daily pain (NRS), weekly median

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    End point title
    		 Numeric Rating of average daily pain (NRS), weekly median
    End point description
    Average daily pain NRS score 0-10, 0 = no pain and 10 = worst possible pain.
    End point type
    Primary
    End point timeframe
    Weekly median of the average daily pain from the each of the 6 weeks in each treatment period and the 2 baseline periods were included in the analysis.
    End point values
    		 Baseline to bupropion Baseline to placebo Bupropion Placebo Intention to treat analysis
    Number of subjects analysed
    59 [1]
    59
    59 [2]
    59
    118
    Units: NRS 0-10 points
        arithmetic mean (standard deviation)
    6.36 ( 0.16 )
    6.17 ( 0.18 )
    5.52 ( 0.23 )
    5.79 ( 0.23 )
    5.52 ( 0.23 )
    Notes
    [1] - 4 subjects excluded due to missing data (no diary handed in), 1 subject too short datacollection
    [2] - 4 subjects excluded due to missing data (no diary handed in), 1 subject too short datacollection
    Statistical analysis title
    		 Primary outcome in general linear model
    Statistical analysis description
    General linear model Including bupropion treatment weeks 1-6 and corresponding baseline period compared to placebo treatment weeks 1-6 and corresponding baseline period in a cross-over design.
    Comparison groups
    Baseline to bupropion v Baseline to placebo v Bupropion v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After three weeks in each treatment period with bupropion and placebo. At the end of each treatment period. At the follow-up phone call at the end of study. Patients could contact the investigator via phone at any timepoint during the study period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Bupropion
    Reporting group description
    		 End of treatment with bupropion

    Reporting group title
    Placebo
    Reporting group description
    		 End of treatment with placebo

    Serious adverse events
    		 Bupropion Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 59 (1.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Necrosis ischaemic
    Additional description: Necrosis of toe related to diabetes mellitus. Planned amputation.
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bupropion Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 62 (54.84%)
    20 / 59 (33.90%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 62 (8.06%)
    11 / 59 (18.64%)
         occurrences all number
    5
    11
    paresthesia
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 62 (11.29%)
    0 / 59 (0.00%)
         occurrences all number
    7
    0
    Dry mouth
         subjects affected / exposed
    5 / 62 (8.06%)
    0 / 59 (0.00%)
         occurrences all number
    5
    0
    Abdominal pain
         subjects affected / exposed
    5 / 62 (8.06%)
    3 / 59 (5.08%)
         occurrences all number
    5
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 62 (17.74%)
    5 / 59 (8.47%)
         occurrences all number
    11
    5
    Fatigue
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1

    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
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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