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    Clinical Trial Results:
    Investigation of dose response relationships when using low dose naltrexone (LDN) for the treatment of fibromyalgia

    Summary
    EudraCT number
    		 2016-002081-31
    Trial protocol
    		 DK  
    Global end of trial date
    10 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    Sdr. Boulevard, Odense C, Denmark, 5000
    Public contact
    Karin Plesner, Anæstesiologisk-intensiv afd V, Odense Universitets Hospital, karin.bruun.plesner@rsyd.dk
    Scientific contact
    Karin Plesner, Anæstesiologisk-intensiv afd V, Odense Universitets Hospital, karin.bruun.plesner@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 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test different doses of low dosis naltrexone (LDN) in patients with fibromyalgia and to estimate effective dose in 50% and 95% of cases.
    Protection of trial subjects
    No specific measures
    Background therapy
    		 Subjects were allowed to continue their usual pain medication. Opioids was not allowed during the trial and 8 weeks before inclusion.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Dec 2016
    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: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited in 2 periods: Pre-period: December 12th 2016 to April 26th 2017. (8 subjects included) Trial was interrupted and an amendment was made to the protocol. Study was restarted. Period 1: June 7th 2017 to September 10th 2018. (27 subjects included)

    Pre-assignment
    Screening details
    		 Period 1: 28 subjects screened, 27 subjects included.

    Pre-assignment period milestones
    Number of subjects started
    		 56 [1]
    Number of subjects completed
    		 54

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This i a study with 1 arm only. Currently the system cannot accommodate this specific scenario. Hence we had to workaround this by adding a baseline arm that is considered one group and the end data another group. An equal number of subjects were added to the arms, giving a deviation in number of enrolled subjects. This is done to be able to use the statistical analysis set to report analysis for a single arm.
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline
    Arm description
    		 Baseline
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Treatment LDN
    Arm description
    		 LDN
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naltrexone hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One daily dosage in the evening. Doses between 0,75 mg and 6 mg.

    Number of subjects in period 1
    		Baseline Treatment LDN
    Started
    27
    27
    Completed
    25
    25
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 54 54
    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
        median (full range (min-max))
    		 47 (27 to 59) -
    Gender categorical
    Units: Subjects
        Female
    		 54 54
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline

    Reporting group title
    Treatment LDN
    Reporting group description
    		 LDN

    Primary: Effective dose in 50%

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    End point title
    		 Effective dose in 50%
    End point description
    The end point is estimated based on the effect of different doses in the 25 subjects who completed the treatment period of 3 weeks, calculated based on the Up-and-down method.
    End point type
    Primary
    End point timeframe
    From restart of the study after amendment to the protocol was made: From June 7th 2017 to September 10th 2018
    End point values
    		 Baseline Treatment LDN
    Number of subjects analysed
    25
    25
    Units: 3.88
        arithmetic mean (confidence interval 95%)
    3.88 (3.39 to 4.35)
    3.88 (3.39 to 4.35)
    Statistical analysis title
    		 Up-and-Down method
    Comparison groups
    Baseline v Treatment LDN
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Up-and-down method
    Parameter type
    		 PAVA estimate
    Point estimate
    3.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.39
         upper limit
    		 4.35
    Variability estimate
    Standard deviation
    Notes
    [1] - Up-and-down method

    Primary: Effective dose in 95 %

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    End point title
    		 Effective dose in 95 %
    End point description
    The end point is estimated based on the effect of different doses in the 25 subjects who completed the treatment period of 3 weeks, calculated based on the Up-and-down method.
    End point type
    Primary
    End point timeframe
    From restart of the study after amendment to the protocol was made: From June 7th 2017 to September 10th 2018
    End point values
    		 Baseline Treatment LDN
    Number of subjects analysed
    25
    25
    Units: 5.40
        arithmetic mean (confidence interval 95%)
    5.4 (4.66 to 6.13)
    5.4 (4.66 to 6.13)
    Statistical analysis title
    		 Up-and-Down method
    Comparison groups
    Baseline v Treatment LDN
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 PAVA estimate
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.66
         upper limit
    		 6.13
    Variability estimate
    Standard deviation
    Notes
    [2] - Up-and-down method

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events reported at: Baseline, 2 weeks, 4 weeks.
    Adverse event reporting additional description
    Regular interviews. Questionnaire about symptoms.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    V22.1
    Reporting groups
    Reporting group title
    Overall group
    Reporting group description
    		 -

    Serious adverse events
    		 Overall group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 27 (92.59%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    4
    Dizziness
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Sleep deficit
    Additional description: Vivid dreams or restlessness during sleep
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 27 (25.93%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Increased appetite
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2017
    Change of primary endpoint. Positive effect of treatment assessed by Patient Global Impression of Improvement on a 7-point Likert scale with the ancors: Very much worse, worse, little worse, no change, little better, better, very much better. Positive effect if: Little better, better, very much better.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Apr 2017
    Study interrupted because the chosen primary outcome fails to identify the subjects who reports a clinical relevant positive effect of the treatment.
    07 Jun 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Given the sequential method we had to evaluate effect of the treatment after a relatively short period of time, and 2 weeks was chosen based on time-response curves from previous trials.
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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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