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    Clinical Trial Results:
    Lyme borreliosis; a scientific approach to reduce diagnostic and therapeutic uncertainties (BorrSci) WP2; SIX VERSUS TWO WEEKS TREATMENT WITH DOXYCYCLINE IN LYME NEUROBORRELIOSIS; A MULTICENTER, NON-INFERIORITY, PENTA-BLIND, RANDOMIZED TRIAL

    Summary
    EudraCT number
    		 2015-001481-25
    Trial protocol
    		 NO  
    Global end of trial date
    21 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2022
    First version publication date
    22 Oct 2022
    Other versions
    Summary report(s)
    		 Six versus 2 weeks treatment with doxycycline in European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blinded, randomised and placebo-controlled trial
    BorrSci Primary endpoint

    Trial information

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    Trial identification
    Sponsor protocol code
    BorrSciWP2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sørlandet Hospital HF
    Sponsor organisation address
    Egsveien 100, Kristiansand, Norway,
    Public contact
    Coordinating investigator, Sørlandet Sykehus HF, 47 41208824, unn.ljostad@sshf.no
    Scientific contact
    Coordinating investigator, Sørlandet Sykehus HF, 47 41208824, unn.ljostad@sshf.no
    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
    07 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To answer the question “is two weeks of doxycycline treatment (currently suggested treatment) at least as effective as six weeks doxycycline treatment in Lyme Neuroborreliosis?”
    Protection of trial subjects
    The patients were followed closely during and after treatment to monitor safety. They were contacted by phone 1 week after start of treatment and questioned about symptom severity and possible side effects. Blood sampling with a status of haematology, liver and kidney function to monitor potential side effects takes place at 2 and 4 weeks after start of treatment. The patients were also asked to fill out a patient diary on symptoms and possible side effects once a week for 10 weeks. In cases of possible disease progression, the patients were evaluated by a physician.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 121
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    88
    From 65 to 84 years
    32
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 One hundred and twenty-one patients were included from 8 Norwegian hospitals. Fifty-two treated for 2 weeks and 53 for 6 weeks were included in the intention-to- treat analyses, and 52 and 51 in per-protocol analysis.

    Pre-assignment
    Screening details
    		 Patients with definite or possible neuroborreliosis according to EFNS guidelines were screened for eligibility to include. At least 144 patients were screened in the inclusion period. We have a complete screening log from the primary inclusion site and 23 patients were considered ineligible for different reasons, including exclusion criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    Blinding implementation details
    Patients were randomised into two treatment arms: oral doxycycline 200 mg once daily for 2 weeks, followed by 4 weeks of placebo, or doxycycline 200 mg once daily for 6 weeks. All patients received identically designed tablets and capsules for 6 weeks. The blinding was retained until all patients had completed the 6 months visit, the content of all tables and figures were fixed, and the statistical procedures were performed with the two treatment arms marked as groups A and B.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 weeks treatment
    Arm description
    		 2 weeks of unblinded doxycyline, followed by 4 weeks of placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg daily, orally for 14 days

    Arm title
    		 6 weeks treatment
    Arm description
    		 2 weeks unblinded treatment with doxycycline, followed by 4 weeks treatment with doxycycline
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg of doxycycline daily for 6 weeks orally

    Number of subjects in period 1
    		2 weeks treatment 6 weeks treatment
    Started
    60
    61
    Completed
    55
    54
    Not completed
    5
    7
         Consent withdrawn by subject
    2
    4
         Other diagnosis discovered after inclusion
    2
    2
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2 weeks treatment
    Reporting group description
    		 2 weeks of unblinded doxycyline, followed by 4 weeks of placebo

    Reporting group title
    6 weeks treatment
    Reporting group description
    		 2 weeks unblinded treatment with doxycycline, followed by 4 weeks treatment with doxycycline

    Reporting group values
    		 2 weeks treatment 6 weeks treatment Total
    Number of subjects
    		 60 61 121
    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, years 2 weeks group: 58 (12) 6 weeks group: 55 (15)
    Units: years
        geometric mean (standard deviation)
    		 58 ( 12 ) 55 ( 15 ) -
    Gender categorical
    Sex Female in 2 weeks group: 21 (40%) 6 weeks group: 25 (47%) Male in 2 weeks groups: 31 (60%) 6 weeks group: 28 (53%)
    Units: Subjects
        Female
    		 25 29 54
        Male
    		 35 32 67

    End points

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    End points reporting groups
    Reporting group title
    2 weeks treatment
    Reporting group description
    		 2 weeks of unblinded doxycyline, followed by 4 weeks of placebo

    Reporting group title
    6 weeks treatment
    Reporting group description
    		 2 weeks unblinded treatment with doxycycline, followed by 4 weeks treatment with doxycycline

    Primary: determine if treatment duration of 2 weeks doxycycline is as effective as a prolonged regimen of 6 weeks

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    End point title
    		 determine if treatment duration of 2 weeks doxycycline is as effective as a prolonged regimen of 6 weeks
    End point description
    The CSS measures 10 subjective symptoms and 22 objective neurological findings. Each of the 32 items is scored as 0=none, 1=mild (without influence on daily life) or 2=severe (with influence on daily life), and the sum score range from 0 to 64.
    End point type
    Primary
    End point timeframe
    The primary endpoint was clinical improvement 6 months after treatment start as measured by difference in CCS sum score from baseline to 6 months.
    End point values
    		 2 weeks treatment 6 weeks treatment
    Number of subjects analysed
    52
    51
    Units: Composite Clinical Score
        geometric mean (confidence interval 95%)
    6.3 (5.6 to 7.1)
    6.7 (6.0 to 7.4)
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    General linear model with treatment group as a factor, and adjustment for duration of symptoms, baseline score, gender and age.
    Comparison groups
    2 weeks treatment v 6 weeks treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 General linear model
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    For each patient the standard time period for collecting and recording AE and SAEs will begin at start of study treatment and will continue during follow up period for at least four weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Frequency threshold for reporting non-serious adverse events: 0%
    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: All registered side effects from the study medication were known from the doxycycline SPC. No serious adverse events were registered.

    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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