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    Clinical Trial Results:
    Randomized double-blind, placebo-controlled parallel group study over 12 months to assess the effects of treatment with benfotiamine on morphometric, neurophysiological, and clinical measures in type 2 diabetes patients with mild to moderate symptomatic polyneuropathy - BOND Study

    Summary
    EudraCT number
    		 2017-003054-16
    Trial protocol
    		 DE  
    Global end of trial date
    13 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2025
    First version publication date
    30 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DDZ-BOND-2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Wörwag Pharma GmbH & co. KG
    Sponsor organisation address
    Flugfeld-Allee 24, Böblingen, Germany, 71034
    Public contact
    Head of Global Clinical Research, Wörwag Pharma GmbH & co. KG, 0049 070316204416, claudia.reule@woerwagpharma.com
    Scientific contact
    Head of Global Clinical Research, Wörwag Pharma GmbH & co. KG, 0049 070316204416, claudia.reule@woerwagpharma.com
    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 Mar 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Mar 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of treatment with benfotiamine compared to placebo for 1 year on morphometric, neurophysiological, and clinical measures in type 2 diabetes patients with mild to moderate symptomatic sensorimotor polyneuropathy.
    Protection of trial subjects
    The trial was in compliance with the ethical principles outlined in the Declaration of Helsinki and the International Council for Harmonisation's Good Clinical Practice (ICH GCP) guidelines. Additionally, all local regulatory requirements related to participant safety were followed throughout the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 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
    Germany: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    26
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 FPFV: 18.10.2018 LPLV: 13.03.2024 Recruitment stop due to COVID19 pandemic: 16.03.2020-18.05.2020 and 13.01.2021-01.02.2021

    Pre-assignment
    Screening details
    		 Screening of participants was based on the evaluation of the inclusion and exclusion criteria. A total of 122 participants were screened and 64 of them did not meet the inclusion 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
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blood thiamin levels were not accessible until the end of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 12 months of treatment with placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosing scheme according to the clinical trial protocol in its latest version is shown in Table 4. This dosing scheme is to be applied by all randomized trial participants. The medication was to be taken as one tablet in the morning (6 am - 10 am), and one tablet in the evening (6 pm - 10 pm) unchewed with enough liquid, on a daily basis.

    Arm title
    		 Benfotiamine
    Arm description
    		 12 months of treatment with benfotiamine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Milgamma® mono 300
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In the current study, all participants were randomised to receive 600 mg of Benfotiamine or the corresponding dose of placebo. The dosing scheme according to the clinical trial protocol in its latest version is shown in Table 4. This dosing scheme is to be applied by all randomized trial participants. The medication was to be taken as one tablet in the morning (6 am - 10 am), and one tablet in the evening (6 pm - 10 pm) unchewed with enough liquid, on a daily basis.

    Number of subjects in period 1
    		Placebo Benfotiamine
    Started
    29
    28
    Completed
    24
    22
    Not completed
    5
    6
         Adverse Event, serious non-fatal
    -
    2
         Drop Out
    5
    4

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 57 57
    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)
    		 26 26
        From 65-84 years
    		 31 31
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (58 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 47 47
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants having at least one dose of treatment and at least one measurement of the primary endpoint under treatment. The efficacy evaluation in this report focuses on the results of the ITT analysis. Criteria for “Intention to treat” were fulfilled by 27 in the placebo group. 2 Participants didn’t fulfil the ITT criteria because they finished the trial before having a measurement of the primary endpoint under treatment and therefore, were not included into efficacy analysis.

    Subject analysis set title
    Benfotiamine
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants having at least one dose of treatment and at least one measurement of the primary endpoint under treatment. The efficacy evaluation in this report focuses on the results of the ITT analysis. Criteria for “Intention to treat” were fulfilled by 24 in the befotiamine grou. Four participants didn’t fulfil the ITT criteria because they finished the trial before having a measurement of the primary endpoint under treatment and therefore, were not included into efficacy analysis.

    Subject analysis sets values
    		 Placebo Benfotiamine
    Number of subjects
    27
    24
    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)
    13
    9
        From 65-84 years
    14
    15
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    65 (58 to 73)
    68.5 (62.5 to 71.5)
    Gender categorical
    Units: Subjects
        Female
    3
    7
        Male
    24
    17

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 12 months of treatment with placebo

    Reporting group title
    Benfotiamine
    Reporting group description
    		 12 months of treatment with benfotiamine

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants having at least one dose of treatment and at least one measurement of the primary endpoint under treatment. The efficacy evaluation in this report focuses on the results of the ITT analysis. Criteria for “Intention to treat” were fulfilled by 27 in the placebo group. 2 Participants didn’t fulfil the ITT criteria because they finished the trial before having a measurement of the primary endpoint under treatment and therefore, were not included into efficacy analysis.

    Subject analysis set title
    Benfotiamine
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all participants having at least one dose of treatment and at least one measurement of the primary endpoint under treatment. The efficacy evaluation in this report focuses on the results of the ITT analysis. Criteria for “Intention to treat” were fulfilled by 24 in the befotiamine grou. Four participants didn’t fulfil the ITT criteria because they finished the trial before having a measurement of the primary endpoint under treatment and therefore, were not included into efficacy analysis.

    Primary: PRIMARY ENDPOINT: CORNEAL NERVE FIBER LENGTH (CNFL)

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    End point title
    		 PRIMARY ENDPOINT: CORNEAL NERVE FIBER LENGTH (CNFL)
    End point description
    The primary aim of the trial was to demonstrate that the corneal nerve fiber length (CNFL) can be improved by the regular intake of 600 mg of benfotiamine for 12 months compared to placebo. The CNFL measurement focuses on the total length of all nerve fibers and branches within the area of corneal tissue. CNFL was measured by using laser scanning corneal confocal microscopy (CCM) examination with the HRT III Rostock Cornea module in vivo corneal confocal microscope (Heidelberg Engineering, Heidelberg, Germany). CCM was measured and scored according to a DDZ SOP. Measurement was performed by sub-investigators only and evaluation by study staff. The study staff selected 6 representative images which were entered into the ACCMetrics software for automatic analysis. CNFL have proven to be highly reproducible and to be closely associated with the severity of DSPN. CCM was performed at baseline, after 6 months (visit 5) and after 12 months (visit 7) of treatment.
    End point type
    Primary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: mm/mm2
        arithmetic mean (standard deviation)
    0.84 ( 3.54 )
    0.56 ( 3.58 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Statistical analysis description
    Differences of baseline to post-treatment changes after 12 months between treatment arms were planned to be analysed by means of analysis of covariance (ANCOVA), where the post-treatment outcome entered the model as the dependent variable and a treatment indicator and the baseline outcome, age, gender, covid-19 information (pre and during covid-19 pandemic) and concomitant medication with gabapentin, pregabalin or duloxetine entered as independent variables.
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - P values: Unadjusted analysis (t Test): 0.314; Adjusted analysis (ANCOVA): 0.806; Adjusted analysis (ANCOVA) after multiple imputation: 0.760

    Secondary: CORNEAL NERVE FIBER DENSITY (CNFD)

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    End point title
    		 CORNEAL NERVE FIBER DENSITY (CNFD)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: mm/mm2
        arithmetic mean (standard deviation)
    0.50 ( 4.62 )
    -0.94 ( 4.21 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine2
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479
    Method
    		 ANCOVA
    Confidence interval

    Secondary: CORNEAL NERVE BRANCH DENSITY (CNBD)

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    End point title
    		 CORNEAL NERVE BRANCH DENSITY (CNBD)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: mm/mm2
        arithmetic mean (standard deviation)
    10.40 ( 19.71 )
    3.22 ( 14.99 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.309
    Method
    		 ANCOVA
    Confidence interval

    Secondary: CORNEAL NERVE FIBER TORTUOSITY (CNFT)

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    End point title
    		 CORNEAL NERVE FIBER TORTUOSITY (CNFT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.01 ( 0.07 )
    -0.00 ( 0.06 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Benfotiamine v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.531
    Method
    		 ANCOVA
    Confidence interval

    Secondary: INTRAEPIDERMAL NERVE FIBER DENSITY (IENFD)

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    End point title
    		 INTRAEPIDERMAL NERVE FIBER DENSITY (IENFD)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: fibers/mm
        arithmetic mean (standard deviation)
    -0.70 ( 2.78 )
    -1.30 ( 1.99 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.484
    Method
    		 ANCOVA
    Confidence interval

    Secondary: ENDOTHELIAL CELL AREA-CLUSTER OF DIFFERENTIATION 31 (CD31)

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    End point title
    		 ENDOTHELIAL CELL AREA-CLUSTER OF DIFFERENTIATION 31 (CD31)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: %
        arithmetic mean (standard deviation)
    -0.09 ( 2.37 )
    -0.38 ( 1.45 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.775
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MITOCHONDRIAL SUPEROXIDE DISMUTASE AREA (SOD2)

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    End point title
    		 MITOCHONDRIAL SUPEROXIDE DISMUTASE AREA (SOD2)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: %
        arithmetic mean (standard deviation)
    -0.35 ( 2.06 )
    -0.28 ( 0.83 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.792
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MOTOR NERVE CONDUCTION VELOCITY (MNCV) SUM SCORE

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    End point title
    		 MOTOR NERVE CONDUCTION VELOCITY (MNCV) SUM SCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    2.92 ( 14.09 )
    -2.43 ( 11.53 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SENSORY NERVE CONDUCTION VELOCITY (SNCV) SUM SCORE

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    End point title
    		 SENSORY NERVE CONDUCTION VELOCITY (SNCV) SUM SCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    2.87 ( 14.10 )
    -2.29 ( 11.60 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.919
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NERVE CONDUCTION VELOCITY (NCV) SUM SCORE

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    End point title
    		 NERVE CONDUCTION VELOCITY (NCV) SUM SCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    2.91 ( 14.09 )
    -2.38 ( 11.55 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.979
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MEAN VALUE VIBRATION PERCEPTION THRESHOLD (VPT) CARPAL

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    End point title
    		 MEAN VALUE VIBRATION PERCEPTION THRESHOLD (VPT) CARPAL
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: μm
        arithmetic mean (standard deviation)
    -0.09 ( 1.00 )
    0.25 ( 1.96 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.526
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MEAN VALUE VIBRATION PERCEPTION THRESHOLD (VPT) MALLEOLAR

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    End point title
    		 MEAN VALUE VIBRATION PERCEPTION THRESHOLD (VPT) MALLEOLAR
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 month of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: μm
        arithmetic mean (standard deviation)
    -1.15 ( 4.89 )
    -1.88 ( 4.21 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.609
    Method
    		 ANCOVA
    Confidence interval

    Secondary: COLD DETECTION THRESHOLD (CDT) THENAR

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    End point title
    		 COLD DETECTION THRESHOLD (CDT) THENAR
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: °C
        arithmetic mean (standard deviation)
    0.16 ( 1.73 )
    0.04 ( 1.42 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.437
    Method
    		 ANCOVA
    Confidence interval

    Secondary: WARMTH DETECTION THRESHOLD (WDT) THENAR

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    End point title
    		 WARMTH DETECTION THRESHOLD (WDT) THENAR
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: °C
        arithmetic mean (standard deviation)
    -0.81 ( 2.25 )
    -0.04 ( 1.37 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.328
    Method
    		 ANCOVA
    Confidence interval

    Secondary: COLD DETECTION THRESHOLD (CDT) FOOT

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    End point title
    		 COLD DETECTION THRESHOLD (CDT) FOOT
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: °C
        arithmetic mean (standard deviation)
    0.21 ( 8.44 )
    1.26 ( 6.38 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.903
    Method
    		 ANCOVA
    Confidence interval

    Secondary: WARMTH DETECTION THRESHOLD (WDT) FOOT

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    End point title
    		 WARMTH DETECTION THRESHOLD (WDT) FOOT
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: °C
        arithmetic mean (standard deviation)
    -0.91 ( 4.83 )
    0.98 ( 4.55 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.966
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SYSTOLIC BLOOD PRESSURE (SBP) IN RESPONSE TO STANDING

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    End point title
    		 SYSTOLIC BLOOD PRESSURE (SBP) IN RESPONSE TO STANDING
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.33 ( 10.45 )
    -0.93 ( 9.14 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.274
    Method
    		 ANCOVA
    Confidence interval

    Secondary: BAROREFLEX SENSITIVITY POSITIVE SLOPE (BRS+/+)

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    End point title
    		 BAROREFLEX SENSITIVITY POSITIVE SLOPE (BRS+/+)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    6.16 ( 28.39 )
    3.32 ( 19.11 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 ANCOVA
    Confidence interval

    Secondary: BAROREFLEX SENSITIVITY NEGATIVE SLOPE (BRS-/-)

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    End point title
    		 BAROREFLEX SENSITIVITY NEGATIVE SLOPE (BRS-/-)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    -1.29 ( 12.36 )
    -0.78 ( 8.97 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.947
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SEQUENCE ANALYSIS BAROREFLEX SENSITIVITY (BRS-ALLSEQ)

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    End point title
    		 SEQUENCE ANALYSIS BAROREFLEX SENSITIVITY (BRS-ALLSEQ)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    4.79 ( 28.54 )
    0.60 ( 11.49 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.581
    Method
    		 ANCOVA
    Confidence interval

    Secondary: LOW FREQUENCE BAROREFLEX SENSITIVITY (BRS-LF)

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    End point title
    		 LOW FREQUENCE BAROREFLEX SENSITIVITY (BRS-LF)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    4.50 ( 28.59 )
    1.08 ( 12.22 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.488
    Method
    		 ANCOVA
    Confidence interval

    Secondary: HIGH FREQUENCE BAROREFLEX SENSITIVITY (BRS-HF)

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    End point title
    		 HIGH FREQUENCE BAROREFLEX SENSITIVITY (BRS-HF)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    4.54 ( 28.58 )
    0.96 ( 12.64 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Benfotiamine v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.926
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SPONTANEOUS BAROREFLEX SENSITIVITY ALPHA (BRS-ALPHA)

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    End point title
    		 SPONTANEOUS BAROREFLEX SENSITIVITY ALPHA (BRS-ALPHA)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    4.52 ( 28.59 )
    1.02 ( 12.28 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.867
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SPONTANEOUS BAROREFLEX SENSITIVITY CROSS-SPECTRAL ANALYSIS (XBRS)

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    End point title
    		 SPONTANEOUS BAROREFLEX SENSITIVITY CROSS-SPECTRAL ANALYSIS (XBRS)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: ms/mmHg
        arithmetic mean (standard deviation)
    0.22 ( 3.78 )
    0.39 ( 5.30 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.978
    Method
    		 ANCOVA
    Confidence interval

    Secondary: STANDARD DEVIATION DERIVED BAROREFLEX SENSITIVITY (BRS-SD)

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    End point title
    		 STANDARD DEVIATION DERIVED BAROREFLEX SENSITIVITY (BRS-SD)
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    1.52 ( 2.87 )
    1.98 ( 3.54 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.232
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPAD QUANTITATIVE EVALUATION ROSE

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    End point title
    		 NEUROPAD QUANTITATIVE EVALUATION ROSE
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: %
        arithmetic mean (standard deviation)
    -8.20 ( 60.01 )
    -30.12 ( 52.71 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.347
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPAD QUANTITATIVE EVALUATION BLUE

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    End point title
    		 NEUROPAD QUANTITATIVE EVALUATION BLUE
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: %
        arithmetic mean (standard deviation)
    8.24 ( 60.02 )
    30.57 ( 52.44 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Benfotiamine v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.195
    Method
    		 ANCOVA
    Confidence interval

    Secondary: ELECTROCHEMICAL SKIN CONDUCTANCE (ESC) HANDS

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    End point title
    		 ELECTROCHEMICAL SKIN CONDUCTANCE (ESC) HANDS
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: μS
        arithmetic mean (standard deviation)
    -3.00 ( 16.70 )
    0.93 ( 15.17 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.374
    Method
    		 ANCOVA
    Confidence interval

    Secondary: ELECTROCHEMICAL SKIN CONDUCTANCE (ESC) FEET

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    End point title
    		 ELECTROCHEMICAL SKIN CONDUCTANCE (ESC) FEET
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2 (randomization) to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: μS
        arithmetic mean (standard deviation)
    -0.98 ( 14.44 )
    -6.68 ( 15.70 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.524
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPATHY DISABILITY SCORE (NDS)

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    End point title
    		 NEUROPATHY DISABILITY SCORE (NDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.79 ( 1.56 )
    0.14 ( 1.73 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.647
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPATHY IMPAIRMENT SCORE – LOWER LIMBS (NIS-LL)

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    End point title
    		 NEUROPATHY IMPAIRMENT SCORE – LOWER LIMBS (NIS-LL)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.46 ( 2.43 )
    0.55 ( 1.79 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MICHIGAN NEUROPATHY SCREENING INSTRUMENT (MNSI) TOTALSCORE

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    End point title
    		 MICHIGAN NEUROPATHY SCREENING INSTRUMENT (MNSI) TOTALSCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.33 ( 1.26 )
    0.05 ( 1.10 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.704
    Method
    		 ANCOVA
    Confidence interval

    Secondary: MODIFIED TORONTO CLINICAL NEUROPATHY SCORE (MTCNS) TOTALSCORE

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    End point title
    		 MODIFIED TORONTO CLINICAL NEUROPATHY SCORE (MTCNS) TOTALSCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.33 ( 4.34 )
    0.32 ( 5.16 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.668
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPATHY SYMPTOM SCORE (NSS)

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    End point title
    		 NEUROPATHY SYMPTOM SCORE (NSS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.33 ( 1.49 )
    -0.59 ( 2.54 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 ANCOVA
    Confidence interval

    Secondary: TOTAL SYMPTOM SCORE (TSS) SHANK

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    End point title
    		 TOTAL SYMPTOM SCORE (TSS) SHANK
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.26 ( 2.58 )
    1.21 ( 3.70 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.616
    Method
    		 ANCOVA
    Confidence interval

    Secondary: TOTAL SYMPTOM SCORE (TSS) FEET

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    End point title
    		 TOTAL SYMPTOM SCORE (TSS) FEET
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.14 ( 2.61 )
    0.32 ( 4.13 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.465
    Method
    		 ANCOVA
    Confidence interval

    Secondary: NEUROPATHIC PAIN SYMPTOM INVENTORY (NPSI) SUMSCORE

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    End point title
    		 NEUROPATHIC PAIN SYMPTOM INVENTORY (NPSI) SUMSCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -3.08 ( 13.20 )
    0.64 ( 20.28 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.967
    Method
    		 ANCOVA
    Confidence interval

    Secondary: 11-POINT NUMERICAL PAIN RATING SCALE (NRS) PAIN 24H

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    End point title
    		 11-POINT NUMERICAL PAIN RATING SCALE (NRS) PAIN 24H
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.17 ( 1.27 )
    0.55 ( 3.29 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.777
    Method
    		 ANCOVA
    Confidence interval

    Secondary: 11-POINT NUMERICAL PAIN RATING SCALE PAIN NIGHT

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    End point title
    		 11-POINT NUMERICAL PAIN RATING SCALE PAIN NIGHT
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.25 ( 3.07 )
    0.18 ( 3.83 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Benfotiamine v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.631
    Method
    		 ANCOVA
    Confidence interval

    Secondary: 11-POINT NUMERICAL PAIN RATING SCALE (NRS) PAIN DAY

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    End point title
    		 11-POINT NUMERICAL PAIN RATING SCALE (NRS) PAIN DAY
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.25 ( 1.82 )
    0.77 ( 3.16 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.634
    Method
    		 ANCOVA
    Confidence interval

    Secondary: BRIEF PAIN INVENTORY (BPI) SEVERITY SCORE

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    End point title
    		 BRIEF PAIN INVENTORY (BPI) SEVERITY SCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.58 ( 2.60 )
    0.63 ( 2.14 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.693
    Method
    		 ANCOVA
    Confidence interval

    Secondary: BRIEF PAIN INVENTORY (BPI) INTERFERENCE SCORE

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    End point title
    		 BRIEF PAIN INVENTORY (BPI) INTERFERENCE SCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.52 ( 2.65 )
    -0.12 ( 1.59 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.846
    Method
    		 ANCOVA
    Confidence interval

    Secondary: EUROQOL 5 DIMENSIONS, 5 LEVELS QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) EQ INDEX

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    End point title
    		 EUROQOL 5 DIMENSIONS, 5 LEVELS QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) EQ INDEX
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -0.01 ( 0.18 )
    -0.00 ( 0.20 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.868
    Method
    		 ANCOVA
    Confidence interval

    Secondary: EUROQOL 5 DIMENSIONS, 5 LEVELS QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) EQ VISUAL ANALOG SCALE (EQ VAS)

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    End point title
    		 EUROQOL 5 DIMENSIONS, 5 LEVELS QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) EQ VISUAL ANALOG SCALE (EQ VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -3.92 ( 26.23 )
    -0.05 ( 22.73 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.749
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SF-36 PHYSICAL COMPONENT SUMMARY

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    End point title
    		 SF-36 PHYSICAL COMPONENT SUMMARY
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.18 ( 7.03 )
    -0.82 ( 10.69 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.881
    Method
    		 ANCOVA
    Confidence interval

    Secondary: SF-36 MENTAL COMPONENT SUMMARY

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    End point title
    		 SF-36 MENTAL COMPONENT SUMMARY
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    -1.17 ( 8.00 )
    -1.28 ( 8.53 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.636
    Method
    		 ANCOVA
    Confidence interval

    Secondary: PATIENT HEALTH QUESTIONNAIRE (PHQ-9) TOTALSCORE

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    End point title
    		 PATIENT HEALTH QUESTIONNAIRE (PHQ-9) TOTALSCORE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: -
        arithmetic mean (standard deviation)
    0.58 ( 2.52 )
    0.00 ( 3.70 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.756
    Method
    		 ANCOVA
    Confidence interval

    Secondary: THIAMINE DIPHOSPHATE (TDP)

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    End point title
    		 THIAMINE DIPHOSPHATE (TDP)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: nMol/l
        arithmetic mean (standard deviation)
    40.00 ( 96.24 )
    191.09 ( 97.36 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: <0.0001

    Secondary: THIAMINE MONOPHOSPHATE (TMP)

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    End point title
    		 THIAMINE MONOPHOSPHATE (TMP)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: nMol/l
        arithmetic mean (standard deviation)
    0.29 ( 3.43 )
    8.18 ( 6.78 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: <0.0001

    Secondary: FREE THIAMINE (FT)

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    End point title
    		 FREE THIAMINE (FT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: nMol/l
        arithmetic mean (standard deviation)
    16.88 ( 80.80 )
    326.73 ( 149.59 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [4] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: <0.0001

    Secondary: TRANSKETOLASE ACTIVITY

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    End point title
    		 TRANSKETOLASE ACTIVITY
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: U/I
        arithmetic mean (standard deviation)
    -3.54 ( 13.78 )
    27.06 ( 50.74 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [5]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: 0.003

    Secondary: THIAMIN PYROPHOSPHAT (TPP) EFFECT

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    End point title
    		 THIAMIN PYROPHOSPHAT (TPP) EFFECT
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: %
        arithmetic mean (standard deviation)
    -0.21 ( 10.64 )
    5.37 ( 56.06 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [6]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: 0.002

    Secondary: TOTAL THIAMINE

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    End point title
    		 TOTAL THIAMINE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: nMol/l
        arithmetic mean (standard deviation)
    40.21 ( 95.69 )
    181.14 ( 91.92 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Placebo v Benfotiamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [7] - P values: Unadjusted analysis (t Test): <0.0001; Adjusted analysis (ANCOVA): <0.0001; Adjusted analysis (ANCOVA) after multiple imputation: <0.0001

    Secondary: LANGERHANS CELL DENSITY (CD207)

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    End point title
    		 LANGERHANS CELL DENSITY (CD207)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months of treatment
    End point values
    		 Placebo Benfotiamine
    Number of subjects analysed
    27
    24
    Units: cells/mm²
        arithmetic mean (standard deviation)
    -14.70 ( 44.81 )
    -44.63 ( 113.86 )
    Statistical analysis title
    		 Changes after 12 months placebo vs. benfotiamine
    Comparison groups
    Benfotiamine v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected before, during and after treatment. Only the adverse events during the treatment will be reported in this report.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Benfotiamine
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Benfotiamine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 29 (17.24%)
    6 / 28 (21.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign duodenal neoplasm
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ductal adenocarcinoma of pancreas
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Spinal decompression
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Inflammatory marker increased
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative delirium
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
    alternative dictionary used: MedDRA 26.1.
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer perforation
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Micturition disorder
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal stenosis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Benfotiamine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 29 (93.10%)
    27 / 28 (96.43%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine neoplasm
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Hypertensive emergency
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 28 (17.86%)
         occurrences all number
    1
    5
    Pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Haematospermia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Premature ejaculation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood albumin increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blood glucose increased
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Blood iron decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blood pressure abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Blood urea increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Carbohydrate antigen 19-9
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 28 (7.14%)
         occurrences all number
    3
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    3 / 29 (10.34%)
    5 / 28 (17.86%)
         occurrences all number
    3
    5
    Lipase increased
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 28 (14.29%)
         occurrences all number
    4
    4
    Weight decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Humerus fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Immunisation reaction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Mouth injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Post procedural haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Postoperative wound complication
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Reactive gastropathy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Skin injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Spinal column injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Tendon rupture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Aortic valve disease mixed
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Burning sensation
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Cerebral microangiopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Headache
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Hypoaesthesia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
         occurrences all number
    3
    4
    Hyporeflexia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    Motor dysfunction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Paraesthesia
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 28 (10.71%)
         occurrences all number
    6
    4
    Sciatica
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Bilateral cataracts
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Macular oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Chronic gastritis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 28 (14.29%)
         occurrences all number
    11
    13
    Diverticulum intestinal
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dyschezia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Gastric ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    3
    Pancreatic disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Pancreatic duct dilatation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Pancreatic failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tooth disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hepatic cyst
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Biliary dilatation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hydrocholecystis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Neurodermatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hidradenitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blister
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Ketonuria
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Microalbuminuria
         subjects affected / exposed
    4 / 29 (13.79%)
    5 / 28 (17.86%)
         occurrences all number
    4
    5
    Proteinuria
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Renal cyst
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Urinary retention
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 28 (14.29%)
         occurrences all number
    2
    8
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 28 (14.29%)
         occurrences all number
    4
    7
    Flank pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    1
    16
    Muscular weakness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Osteitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Osteoarthritis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 28 (17.86%)
         occurrences all number
    6
    5
    Tendon pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    COVID-19
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Cystitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    6
    Focal peritonitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    3
    Gingivitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 29 (31.03%)
    4 / 28 (14.29%)
         occurrences all number
    13
    6
    Pulpitis dental
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Onychomycosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Dec 2018
    Changes in the clinical trial protocol and change in subject compensation
    08 May 2019
    Changes to the inclusion and exclusion criteria
    24 Apr 2020
    Substantial changes in the trial conduct, handling drop-outs/discontinuations and statistical considerations due to COVID-19.
    19 May 2020
    Substantial amendement to clinical study protocol (Note to File #7 to #12); Submission Note to File #1 to #3
    16 Feb 2021
    Approval for resumption of screening visits due to COVID-19 and Amendment to clinical study protocol due to change of deputy investigator and incorporation of COVID-19 note to files.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Recruitment stop due to COVID19 pandemic
    18 May 2020
    13 Jan 2021
    Recruitment stop due to COVID19 pandemic
    01 Feb 2021

    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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