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    Clinical Trial Results:
    The beta-2-agonist terbutaline for the treatment of painful polyneuropathy. A randomised, active- and placebo-controlled trial

    Summary
    EudraCT number
    		 2015-002984-40
    Trial protocol
    		 DK  
    Global end of trial date
    29 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions
    Summary report(s)
    		 BETA2summary

    Trial information

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    Trial identification
    Sponsor protocol code
    beta2
    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 Team, Odense University Hospital, 45 65412471, soeren.sindrup@rsyd.dk
    Scientific contact
    Neuromuscular Team, Odense University Hospital, 45 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
    31 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of the trial is to determine if terbutaline relieves pain in polyneuropathy.
    Protection of trial subjects
    Escape medication paracetamol
    Background therapy
    		 None
    Evidence for comparator
    		 Comparator imipramine (TCA) evidenced in several RCTs.
    Actual start date of recruitment
    01 Oct 2015
    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: 141
    Worldwide total number of subjects
    141
    EEA total number of subjects
    141
    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)
    75
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited from neurology out patient clinics at Odense and Aarhus University Hospitals in Denmark,

    Pre-assignment
    Screening details
    		 Screening period for confirmation of diagnosis of peripheral neuropathic pain, as well as in- and exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 141
    Number of subjects completed
    		 141

    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 terbutaline
    Arm description
    		 Baseline period with no treatment before terbutaline
    Arm type
    		 Baseline no treatment

    Investigational medicinal product name
    no treatment
    Investigational medicinal product code
    None
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    No treatment

    Arm title
    		 Baseline to imipramine
    Arm description
    		 Baseline period with no treatment before imipramine
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Baseline to placebo
    Arm description
    		 Baseline period with no treatment before placebo
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Baseline to terbutaline Baseline to imipramine Baseline to placebo
    Started
    48
    50
    43
    Completed
    46
    48
    41
    Not completed
    2
    2
    2
         low pain score (<4 NRS)
    2
    2
    2
    Period 2
    Period 2 title
    Tretment periods summary
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Placebo capsules identical to terbutaline and imipramine capsules. Double-dummy technique.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Terbutaline
    Arm description
    		 Treatment with terbutaline 5 mg to 15 mg daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Terbutaline capsule 5 mg
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Age <70years 5-15 mg/day Age >= 70 years 5 mg/day

    Arm title
    		 Imipramine
    Arm description
    		 Double-blinded treatment with imipramine 30 mg to 150 mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imipramine 30 mg capsule
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Age < 70 years, fast metbolizer 30-150 mg/day Age < 70 years, poor metabolizer 30 mg/day Age >= 70 years 30 mg/day

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

    Investigational medicinal product name
    Placebo capsule
    Investigational medicinal product code
    PL
    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
    		Terbutaline Imipramine Placebo
    Started
    46
    48
    41
    Completed
    41
    44
    38
    Not completed
    5
    4
    3
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    3
    3
    -
         Other disease
    1
    1
    2
         Lack of efficacy
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Subjects countet for each baseline period

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 141 141
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 111 111
        From 65-84 years
    		 30 30
        85 years and over
    		 0 0
    Age continuous
    Age at baseline period 1
    Units: years
        median (full range (min-max))
    		 59 (20 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 66 66
        Male
    		 75 75
    Subject analysis sets

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

    Subject analysis sets values
    		 Intention to treat popultion
    Number of subjects
    135
    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)
    109
        From 65-84 years
    26
        85 years and over
    0
    Age continuous
    Age at baseline period 1
    Units: years
        median (full range (min-max))
    59 (20 to 76)
    Gender categorical
    Units: Subjects
        Female
    63
        Male
    72

    End points

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

    Reporting group title
    Baseline to imipramine
    Reporting group description
    		 Baseline period with no treatment before imipramine

    Reporting group title
    Baseline to placebo
    Reporting group description
    		 Baseline period with no treatment before placebo
    Reporting group title
    Terbutaline
    Reporting group description
    		 Treatment with terbutaline 5 mg to 15 mg daily

    Reporting group title
    Imipramine
    Reporting group description
    		 Double-blinded treatment with imipramine 30 mg to 150 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo capsules

    Subject analysis set title
    Intention to treat popultion
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intention to treat analysis set, subjects with data from 1 or to 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 5 weeks in each treatment period and the 3 baseline periods were included in the analysis.
    End point values
    		 Baseline to terbutaline Terbutaline Imipramine Placebo Baseline to imipramine Baseline to placebo Intention to treat popultion
    Number of subjects analysed
    41
    41
    44
    38
    44
    38
    41
    Units: NRS 0-10 points
        median (standard deviation)
    6.44 ( 1.83 )
    6.13 ( 2.34 )
    4.77 ( 2.43 )
    5.66 ( 1.91 )
    6.58 ( 1.91 )
    6.27 ( 1.74 )
    6.13 ( 2.34 )
    Statistical analysis title
    		 Primary outcome in general linear model
    Statistical analysis description
    General linear model Including terbutaline treatment weeks 1-5 and correspnding baseline period compared to placebo treatment weeks 1-5 and corresponding basline period,
    Comparison groups
    Terbutaline v Placebo v Baseline to terbutaline v Baseline to placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.032 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.123
         upper limit
    		 0.379
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.126
    Notes
    [1] - 2 comparisons: Terbutaline vs placebo and Terbutaline vs Imipramine The second comparison, i.e. Tebutaline vs Imipramine, showed lower pain scores on imipramine (week 5: 4.77 NRS) than on Terbutaline (week 5: 6.13), p < 0.001

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    End of terbutaline, imipramine and placebo treatment periods.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Terbutaline
    Reporting group description
    		 End of treatment with terbutaline

    Reporting group title
    Imipramine
    Reporting group description
    		 End of imipramine treatment period

    Reporting group title
    Placebo
    Reporting group description
    		 End of placebo treatment period.

    Serious adverse events
    		 Terbutaline Imipramine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 41 (2.44%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection after planed knee surgery
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Terbutaline Imipramine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
    Cardiac disorders
    palpitations
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    6
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    10
    8
    3
    Leg Cramps
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    8
    0
    0
    Tremor
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    7
    0
    0
    Dizziness
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    5
    12
    0
    General disorders and administration site conditions
    Tiredness
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    1
    9
    5
    Vivid dreams
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    1
    0
    0
    Sweating
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    0
    8
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    5
    21
    3
    Constipation
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    0
    8
    3
    Endocrine disorders
    High blood sugar
         subjects affected / exposed
    27 / 46 (58.70%)
    38 / 48 (79.17%)
    17 / 41 (41.46%)
         occurrences all number
    1
    0
    0

    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
    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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