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    Clinical Trial Results:
    A Randomised, Double-Blind, Placebo-Controlled, Dose-Response Study of the Efficacy and Safety of MEDI7352 in Subjects with Painful Diabetic Neuropathy

    Summary
    EudraCT number
    		 2018-002523-42
    Trial protocol
    		 GB   ES   PL   HU   DK   RO  
    Global end of trial date
    29 Jun 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Aug 2024
    First version publication date
    14 Jul 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D5680C00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03755934
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    151 85, Sodertalje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.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 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the efficacy of MEDI7352 versus placebo on chronic pain in subjects with painful diabetic neuropathy (PDN) currently taking standard of care medication for their PDN pain.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 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
    Poland: 62
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Hungary: 10
    Worldwide total number of subjects
    112
    EEA total number of subjects
    78
    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)
    68
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 45 sites in 4 countries (the United Kingdom, Hungary, Poland, and Romania).

    Pre-assignment
    Screening details
    		 A total of 112 participants were randomized, of which 107 participants received at least one dose of study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received intravenous (IV) placebo infusion matched to MEDl7352 during 12-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV placebo infusion matched to MEDl7352 during 12-week treatment period.

    Arm title
    		 MEDl7352 Low Dose
    Arm description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDl7352
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV MEDl7352 given during a 12-week treatment period.

    Arm title
    		 MEDl7352 Medium Dose
    Arm description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDl7352
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV MEDl7352 given during a 12-week treatment period.

    Arm title
    		 MEDI7352 High Dose
    Arm description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDl7352
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV MEDl7352 given during a 12-week treatment period.

    Number of subjects in period 1
    		Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Started
    54
    6
    16
    36
    Treated
    54
    4
    14
    35
    Completed
    40
    4
    12
    30
    Not completed
    14
    2
    4
    6
         Physician decision
    2
    -
    -
    1
         Consent withdrawn by subject
    5
    -
    -
    1
         Adverse event, non-fatal
    4
    1
    1
    3
         Unspecified
    3
    1
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received intravenous (IV) placebo infusion matched to MEDl7352 during 12-week treatment period.

    Reporting group title
    MEDl7352 Low Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Reporting group title
    MEDl7352 Medium Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Reporting group title
    MEDI7352 High Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Reporting group values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose Total
    Number of subjects
    		 54 6 16 36 112
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 35 3 9 21 68
        From 65-84 years
    		 19 3 7 15 44
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.7 ( 8.02 ) 60.7 ( 17.14 ) 60.1 ( 11.49 ) 60.1 ( 10.21 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 20 0 5 15 40
        Male
    		 34 6 11 21 72
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 2 0 2
        White
    		 53 6 14 36 109
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 1 0 0 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 54 6 16 36 112
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received intravenous (IV) placebo infusion matched to MEDl7352 during 12-week treatment period.

    Reporting group title
    MEDl7352 Low Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Reporting group title
    MEDl7352 Medium Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Reporting group title
    MEDI7352 High Dose
    Reporting group description
    		 Participants received IV MEDl7352 infusion during 12-week treatment period.

    Primary: Change From Baseline in Weekly Average of Average Daily Pain Score to Week 12

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    End point title
    		 Change From Baseline in Weekly Average of Average Daily Pain Score to Week 12
    End point description
    Change from baseline to Week 12 in weekly average of average daily pain score is reported. Participants assessed their perceived daily average neuropathic pain over the previous 24 hours using an 11-point numerical rating scale (NRS), with 0 representing no pain and 10 representing the worst pain imaginable. Participants were instructed to assess their average daily pain at approximately the same time every morning, and to record the response in a subject diary (electronic patient-reported outcome [ePRO]). Modified intent-to-treat (mITT) population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment.
    End point type
    Primary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive) through Week 12
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -1.244 ( 1.7327 )
    -3.387 ( 1.9605 )
    -0.615 ( 1.0431 )
    -2.699 ( 2.0819 )
    Statistical analysis title
    		 ANCOVA Analysis
    Comparison groups
    Placebo v MEDl7352 Low Dose
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0437 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean estimate
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.87
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.961
    Notes
    [1] - ANCOVA by dose using NRS baseline value and co-medication as covariates, with CFB to Week 12 (LOCF) as dependent variable was used to derive p-value.
    Statistical analysis title
    		 ANCOVA Analysis
    Comparison groups
    Placebo v MEDl7352 Medium Dose
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1878 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean estimate
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 1.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.541
    Notes
    [2] - ANCOVA by dose using NRS baseline value and co-medication as covariates, with CFB to Week 12 (LOCF) as dependent variable was used to derive p-value.
    Statistical analysis title
    		 ANCOVA Analysis
    Comparison groups
    Placebo v MEDI7352 High Dose
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0009 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean estimate
    Point estimate
    -1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.19
         upper limit
    		 -0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.407
    Notes
    [3] - ANCOVA by dose using NRS baseline value and co-medication as covariates, with CFB to Week 12 (LOCF) as dependent variable was used to derive p-value.

    Secondary: Change From Baseline in Weekly Average of Average Daily Pain Score

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    End point title
    		 Change From Baseline in Weekly Average of Average Daily Pain Score
    End point description
    Change from baseline to Weeks 2, 4, 6, 8, 10, and 18 in weekly average of average daily pain score is reported. Participants assessed their perceived daily average neuropathic pain over the previous 24 hours using an 11-point NRS, with 0 representing no pain and 10 representing the worst pain imaginable. Participants were instructed to assess their average daily pain at approximately the same time every morning, and to record the response in a subject diary (ePRO). mITT population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive), Weeks 2, 4, 6, 8, 10, and 18
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 2 (n=53,4,14,35)
    -0.385 ( 0.6863 )
    -1.089 ( 1.0258 )
    -0.311 ( 0.6285 )
    -0.540 ( 1.2503 )
        Week 4 (n=54,4,13,35)
    -0.563 ( 1.0173 )
    -2.173 ( 1.4266 )
    -0.144 ( 0.9143 )
    -1.508 ( 1.5130 )
        Week 6 (n=50,4,13,34)
    -0.955 ( 1.3236 )
    -2.458 ( 2.2156 )
    -0.578 ( 1.0715 )
    -2.044 ( 1.7916 )
        Week 8 (n=46,4,12,33)
    -1.236 ( 1.6026 )
    -2.393 ( 2.0249 )
    -0.690 ( 1.2819 )
    -2.372 ( 2.0607 )
        Week 10 (n=44,4,12,33)
    -1.418 ( 1.6274 )
    -2.595 ( 2.2003 )
    -0.712 ( 1.2164 )
    -2.629 ( 1.9943 )
        Week 18 (n=40,4,12,30)
    -1.764 ( 1.8415 )
    -2.607 ( 2.2020 )
    -0.550 ( 1.2333 )
    -2.559 ( 2.1241 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With >= 30% and >= 50% Reductions in Weekly Average of Average Daily Pain Score

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    End point title
    		 Percentage of Participants With >= 30% and >= 50% Reductions in Weekly Average of Average Daily Pain Score
    End point description
    Percentage of participants with >=30% and >=50% decrease in weekly average of average daily pain score from baseline is reported. Participants assessed their perceived daily average neuropathic pain over the previous 24 hours using an 11-point NRS, with 0 representing no pain and 10 representing the worst pain imaginable. Participants were instructed to assess their average daily pain at approximately the same time every morning, and to record the response in a subject diary (ePRO). mITT population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive), Weeks 4, 8, 12, and 18 (follow-up)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    13
    35
    Units: Percentage of participants
    number (not applicable)
        >=30%: Week 4 (n=54,4,13,35)
    3.7
    75.0
    7.7
    34.3
        >=30%: Week 8 (n=46,4,12,33)
    28.3
    75.0
    16.7
    57.6
        >=30%: Week 12 (n=43,4,12,33)
    32.6
    75.0
    8.3
    66.7
        >=30%: Week 18 (n=40,4,12,30)
    35.0
    50.0
    25.0
    56.7
        >=50%: Week 4 (n=54,4,13,35)
    1.9
    0
    0
    14.3
        >=50%: Week 8 (n=46,4,12,33)
    13.0
    25.0
    8.3
    36.4
        >=50%: Week 12 (n=43,4,12,33)
    11.6
    50.0
    8.3
    42.4
        >=50%: Week 18 (n=40,4,12,30)
    15.0
    25.0
    0
    40.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Galer Neuropathic Pain Scale (NPS)

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    End point title
    		 Change From Baseline in Galer Neuropathic Pain Scale (NPS)
    End point description
    Change from baseline to Weeks 4, 8, 12, and 18 in Galer NPS total score is reported. Galer NPS included 2 descriptors of pain, including intensity and unpleasantness, and 8 descriptors that assessed specific qualities of neuropathic pain: sharp, hot, dull, cold, sensitive, itchy, deep, and surface pain. Each of these 10 dimensions had a 0 to 10 NRS in which 0 means no pain and 10 means most intense pain. Galer NPS total score (ranges from 0 to 100; with 0 and 100 representing no and highest degree of neuropathic-like symptoms, respectively) is sum of pain intensity, pain unpleasantness, pain sharpness, pain hotness, pain dullness, pain coldness, pain sensitivity, pain itching, deep pain intensity, and surface pain intensity (all in 11-point NRS). mITT population: participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving treatment. Number analyzed (n): participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive), Weeks 4, 8, 12, and 18 (follow-up)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    48
    4
    12
    31
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=48,4,11,31)
    -13.333 ( 29.0461 )
    -5.750 ( 10.5317 )
    -10.727 ( 21.3967 )
    -26.387 ( 26.9922 )
        Week 8 (n=44,4,12,31)
    -19.136 ( 31.5577 )
    -8.750 ( 18.2094 )
    -19.333 ( 23.7538 )
    -29.516 ( 32.3140 )
        Week 12 (n=39,4,11,29)
    -24.385 ( 31.1081 )
    -28.750 ( 16.6808 )
    -22.000 ( 28.9379 )
    -34.586 ( 31.2622 )
        Week 18 (follow-up;n=36,4,11,29)
    -25.722 ( 33.6151 )
    -23.000 ( 23.3095 )
    -27.909 ( 30.3725 )
    -25.414 ( 25.8947 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Daily Sleep Interference Scale (DSIS)

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    End point title
    		 Change From Baseline in Daily Sleep Interference Scale (DSIS)
    End point description
    The DSIS measures sleep interference due to pain. It is a single item measure that is completed by participants once a day (on waking up). It has an 11-point response scale (0-10) that asked participants to “select the number that best describes how much your pain has interfered with your sleep during the past 24 hours”. Responses vary from 0 (did not interfere with sleep) to 10 (completely interfered with sleep-unable to sleep due to pain). Change from baseline to Weeks 4, 8, 12, and 18 (follow-up) in DSIS is reported. mITT population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment. Number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive), Weeks 4, 8, 12, and 18 (follow-up)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    52
    4
    13
    35
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=52,4,13,35)
    -0.760 ( 1.1212 )
    -2.810 ( 2.6979 )
    -0.979 ( 1.7930 )
    -1.790 ( 1.5688 )
        Week 8 (n=46,4,12,33)
    -1.417 ( 1.7654 )
    -3.143 ( 2.7430 )
    -1.127 ( 1.4907 )
    -2.373 ( 2.1368 )
        Week 12 (n=42,4,12,33)
    -1.668 ( 2.1928 )
    -3.735 ( 2.7598 )
    -1.077 ( 1.4769 )
    -2.725 ( 2.2484 )
        Week 18 (follow-up;n=40,4,12,30)
    -1.824 ( 2.2582 )
    -3.036 ( 2.6557 )
    -0.865 ( 1.2795 )
    -2.602 ( 2.4427 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With 'Improved', 'Much Improved', or 'Very Much Improved' Status in Patient Global Impression of Change (PGIC)

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    End point title
    		 Percentage of Participants With 'Improved', 'Much Improved', or 'Very Much Improved' Status in Patient Global Impression of Change (PGIC)
    End point description
    Participants rated their overall improvement in health status using the PGIC. The PGIC consisted of a 7-point scale where 1 = very much improved and 7 = very much worse. The participants were asked the following question: How would you rate your overall improvement with treatment during the clinical study?, where the response options included the following: Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse, and Very Much Worse. mITT population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment. Number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive), Weeks 4, 8, 12, and 18 (follow-up)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    48
    4
    12
    31
    Units: Percentage of participants
    number (not applicable)
        Week 4: Improved (n=48,4,11,31)
    50.0
    50.0
    45.5
    41.9
        Week 4: Much Improved (n=48,4,11,31)
    2.1
    25.0
    27.3
    29.0
        Week 4: Very Much Improved (n=48,4,11,31)
    2.1
    0
    0
    6.5
        Week 8: Improved (n=44,4,12,31)
    36.4
    25.0
    58.3
    41.9
        Week 8: Much Improved (n=44,4,12,31)
    31.8
    50.0
    41.7
    38.7
        Week 8: Very Much Improved (n=44,4,12,31)
    2.3
    0
    0
    6.5
        Week 12: Improved (n=39,4,11,29)
    48.7
    0
    54.5
    44.8
        Week 12 Much Improved (n=39,4,11,29)
    28.2
    75.0
    36.4
    41.4
        Week 12: Very Much Improved (n=39,4,11,29)
    5.1
    25.0
    0
    10.3
        Week 18: Improved (n=36,4,11,29)
    36.1
    25.0
    27.3
    31.0
        Week 18: Much Improved (n=36,4,11,29)
    25.0
    50.0
    54.5
    41.4
        Week 18: Very Much Improved (n=36,4,11,29)
    11.1
    25.0
    9.1
    13.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in 36-item Short-Form Health Survey (SF-36)

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    End point title
    		 Change From Baseline in 36-item Short-Form Health Survey (SF-36)
    End point description
    Change from baseline to Week 12 in SF-36 is reported. The SF-36 assesses 8 health concepts: 1) limitations in physical activities because of health problems (physical functioning); 2) limitations in social activities because of physical or emotional problems (social functioning); 3) limitations in usual role activities because of physical health problems (role physical); 4) bodily pain; 5) general mental health; 6) limitations in usual role activities because of emotional problems (role emotional); 7) vitality; and 8) general health perceptions. The items use Likert-type scales with either 5 or 6 points, or 2 or 3 points. Higher SF-36 scores indicate a better state of health. Score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). mITT population: all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive) and Week 12
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    39
    4
    12
    29
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical Functioning
    11.282 ( 17.0412 )
    21.248 ( 13.1526 )
    0.417 ( 19.7084 )
    12.759 ( 16.6141 )
        Role Physical
    7.372 ( 18.0159 )
    28.125 ( 27.7169 )
    0.000 ( 37.3101 )
    6.681 ( 17.4338 )
        Bodily Pain
    8.3 ( 20.51 )
    9.8 ( 22.75 )
    12.1 ( 23.11 )
    14.9 ( 17.30 )
        General Health
    -2.6 ( 17.70 )
    -2.5 ( 5.00 )
    -5.3 ( 17.72 )
    0.0 ( 19.98 )
        Vitality
    -0.160 ( 20.6039 )
    3.125 ( 16.5359 )
    -0.521 ( 17.7695 )
    -4.095 ( 24.0486 )
        Social Functioning
    1.92 ( 19.772 )
    31.25 ( 23.936 )
    -1.04 ( 24.108 )
    9.05 ( 23.121 )
        Role Emotional
    -1.923 ( 25.3248 )
    8.333 ( 31.9110 )
    -5.556 ( 34.8748 )
    -1.724 ( 19.9681 )
        Mental Health
    -5.9 ( 21.82 )
    10.0 ( 20.41 )
    -1.3 ( 14.48 )
    -0.7 ( 18.41 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Taking any Rescue Medication

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    End point title
    		 Percentage of Participants Taking any Rescue Medication
    End point description
    Percentage of participants taking any rescue medication are reported. Participants were asked to record all rescue medications they take for neuropathic pain in a paper diary. mITT population included all participants who received at least 1 dose of any double-blind study drug and have at least 1 daily NRS assessment while receiving the treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -7 to Day -1, inclusive) through Week 12
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Percentage of participants
        number (not applicable)
    13.0
    0
    14.3
    8.6
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
        Any TEAEs
    30
    4
    10
    23
        Any TESAEs
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Vital Signs Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Vital Signs Reported as TEAEs
    End point description
    Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, diastolic blood pressure, systolic blood pressure, heart rate, and respiratory rate).
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
        Blood pressure increased
    0
    0
    0
    1
        Hypotension
    0
    0
    0
    1
        Hypertension
    1
    0
    0
    0
        Orthostatic hypertension
    1
    0
    0
    0
        Orthostatic hypotension
    3
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)

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    End point title
    		 Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)
    End point description
    Number of participants with clinically significant abnormal ECGs are reported. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
        Day 1 (n=54,4,14,35)
    1
    0
    0
    0
        Week 4 (n=50,4,13,32)
    0
    0
    1
    0
        Week 8 (n=45,4,12,32)
    0
    0
    0
    1
        Week 12 (n=40,4,11,31)
    1
    0
    0
    1
        Week 18 (follow-up;n=40,4,12,30)
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
    End point description
    Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
        Alanine aminotransferase increased
    0
    0
    2
    0
        Blood glucose decreased
    0
    0
    1
    1
        Aspartate aminotransferase increased
    0
    0
    1
    0
        Blood glucose increased
    0
    0
    0
    1
        C-reactive protein increased
    1
    0
    0
    1
        Coagulation test abnormal
    0
    0
    0
    1
        Glomerular filtration rate decreased
    0
    0
    0
    1
        White blood cells urine positive
    0
    0
    0
    1
        Bacterial test positive
    1
    0
    0
    0
        Blood bilirubin increased
    1
    0
    0
    0
        Protein urine present
    1
    0
    0
    0
        Urine analysis abnormal
    1
    0
    0
    0
        Hypoglycaemia
    1
    0
    1
    1
        Hypercholesterolaemia
    0
    0
    0
    1
        Hyperglycaemia
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Findings in Physical Examination Reported as TEAEs

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    End point title
    		 Number of Participants With Clinically Significant Findings in Physical Examination Reported as TEAEs
    End point description
    Number of participants with clinically significant findings in physical examination reported as TEAEs are reported. A complete physical examination (excluding the genitourinary examination, unless warranted) was performed. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    1
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Findings in Neurological Examination

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    End point title
    		 Number of Participants With Clinically Significant Findings in Neurological Examination
    End point description
    Number of participants with clinically significant findings in neurological examination is reported. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Dorsiflexion Strength

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    End point title
    		 Number of Participants With Abnormal Dorsiflexion Strength
    End point description
    Number of participants with abnormal dorsiflexion strength is reported. Dorsiflexion strength is scored on 0-4 scale. The scale indicated 0 = normal power, 1 = mild weakness, 2 = moderate weakness, 3 = severe weakness, and 4 = paralysis. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received. Here, number of participants analyzed (N) denotes those participants who were assessed for strength and deep tendon reflexes assessment.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    40
    4
    12
    30
    Units: Participants
        Mild Weakness
    9
    0
    7
    18
        Moderate Weakness
    8
    0
    0
    2
        Severe Weakness
    0
    0
    0
    0
        Paralysis
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Deep Tendon Reflex (Knee and Ankle)

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    End point title
    		 Number of Participants With Abnormal Deep Tendon Reflex (Knee and Ankle)
    End point description
    Number of participants with abnormal deep tendon reflex are reported. Deep tendon reflex (knee and ankle) strength is scored on 0-4 scale. The scale indicated 0 = normal, 1 = ankle reflex reduced, 2 = ankle reflex absent, 3 = ankle reflex absent and knee reflex reduced, and 4 = all reflexes (both ankle and knee) absent. Participants within a specific row are not included in any other row in the data table below. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received. Here, number of participants analyzed (N) denotes those participants who were assessed for strength and deep tendon reflexes assessment.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    40
    4
    12
    30
    Units: Participants
        Ankle reflex reduced
    5
    2
    2
    3
        Ankle reflex absent
    4
    0
    1
    5
        Ankle reflex absent and knee reflex reduced
    11
    1
    3
    13
        All reflexes absent
    15
    0
    6
    5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Neuropathy Score-Nurse (TNSn)

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    End point title
    		 Change From Baseline in Total Neuropathy Score-Nurse (TNSn)
    End point description
    TNSn, a semi-quantitative clinical assessment of peripheral nervous system function, was administered at baseline, Day 1, Weeks 2, 4, 6, 8, 10, 12, 18/early termination. It provides for assessment of motor and autonomic symptom, pin sensibility, and vibration sensibility score. Each neuropathy item is scored on 0–4 scale. The scores are summed to obtain a total score ranging 0-20, where score of 20 correlate with more severe neuropathy. Arbitrary numbers 99.999, 99999 signified mean and standard deviation (SD), respectively, not reported as no participants were evaluable in arm. Arbitrary number 999.99 signified SD not reported as only 1 participant was evaluable for this arm. Safety population: participants who received at least 1 dose of any double-blind study drug and were analyzed according to treatment actually received. Number analyzed (n): participants who were evaluable at specified time point. Only 3 early terminated participants contributed data at Week 18 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -45 to -1), pre-dose on Day 1, Weeks 2, 4, 6, 8, 10, 12, and 18/early termination
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    50
    4
    13
    34
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Day 1 (n=4,0,0,1)
    -0.25 ( 0.957 )
    99.999 ( 99999 )
    99.999 ( 99999 )
    1.00 ( 999.99 )
        Week 2 (n=48,4,13,34)
    -0.54 ( 1.304 )
    -1.25 ( 1.258 )
    0.00 ( 1.354 )
    -0.94 ( 2.117 )
        Week 4 (n=50,4,13,32)
    -0.90 ( 1.982 )
    -2.50 ( 3.786 )
    -0.85 ( 1.819 )
    -1.19 ( 1.891 )
        Week 6 (n=45,4,12,33)
    -1.40 ( 2.071 )
    -0.75 ( 2.872 )
    -1.00 ( 1.859 )
    -1.85 ( 2.093 )
        Week 8 (n=45,4,12,32)
    -1.40 ( 2.082 )
    -2.50 ( 3.000 )
    -0.92 ( 1.881 )
    -1.84 ( 2.665 )
        Week 10 (n=40,4,12,31)
    -1.90 ( 2.458 )
    -2.00 ( 3.916 )
    -1.67 ( 1.435 )
    -2.45 ( 3.042 )
        Week 12 (n=40,4,12,30)
    -1.73 ( 2.562 )
    -2.25 ( 2.062 )
    -2.17 ( 1.899 )
    -2.53 ( 2.515 )
        Week 18 (n=40,4,12,30)
    -2.00 ( 2.631 )
    -2.50 ( 3.512 )
    -2.17 ( 2.329 )
    -2.30 ( 3.053 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Investigator Reported Significant Changes From Baseline in Motor and Sensory Nerve Conduction

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    End point title
    		 Number of Participants With Investigator Reported Significant Changes From Baseline in Motor and Sensory Nerve Conduction
    End point description
    Motor and sensory nerve conduction studies were performed in relevant lower and upper limb nerves (sural, peroneal, median/ulnar, fibular, and tibial nerves) wherein amplitude, peak latency, conduction velocity, and duration of nerve action potentials were recorded. Safety population included all participants who receivedat least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    2
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With at Least One Concomitant Medication

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    End point title
    		 Number of Participants With at Least One Concomitant Medication
    End point description
    Number of participants with at least one concomitant medication is reported. A concomitant medication is defined as any medication continuing or starting after first dose of study medication. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    54
    4
    14
    35
    No statistical analyses for this end point

    Secondary: Number of Participants With Injection Site Reaction

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    End point title
    		 Number of Participants With Injection Site Reaction
    End point description
    Number of participants with injection site reaction is reported. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    1
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Infusion Reaction

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    End point title
    		 Number of Participants With Infusion Reaction
    End point description
    Number of participants with infusion reaction is reported. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 20.42 weeks (maximum observed duration)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    54
    4
    14
    35
    Units: Participants
    0
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Serum Total Nerve Growth Factor (NGF) Concentrations

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    End point title
    		 Serum Total Nerve Growth Factor (NGF) Concentrations
    End point description
    Serum concentrations of total NGF in ADA positive or negative participants are reported. Data for MEDl7352 low and medium dose group is not reported due to change in assay during the course of the study and stability data not supporting the re-analysis of early study samples with the new in-house assay. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received. Number of participants analyzed (N) denotes the number of participants evaluated for this outcome measure. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose: Day 1 (baseline), Weeks 2, 4, 6, 8; Week 10 (Day 70; pre-dose, immediately before end of infusion, 8 hours post infusion start), Day 71 (post 24 hours of Day 70 infusion start), Weeks 11, 12 (approximately same time of day as Week 10 infusion)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    30
    0 [4]
    0 [5]
    31
    Units: pg/mL
    arithmetic mean (standard deviation)
        Day 1 (n=30,0,0,31)
    52.303 ( 11.6178 )
    ( )
    ( )
    65.687 ( 60.4036 )
        Week 2 (n=29,0,0,29)
    62.613 ( 15.1088 )
    ( )
    ( )
    2384.760 ( 1989.0309 )
        Week 4 (n=29,0,0,29)
    78.209 ( 92.0122 )
    ( )
    ( )
    2213.699 ( 2408.3112 )
        Week 6 (n=27,0,0,29)
    64.661 ( 18.6478 )
    ( )
    ( )
    2361.855 ( 2645.8141 )
        Week 8 (n=26,0,0,29)
    63.291 ( 16.5332 )
    ( )
    ( )
    1992.129 ( 2507.9826 )
        Week 10 (pre-dose; n=25,0,0,28)
    173.383 ( 563.8921 )
    ( )
    ( )
    1681.073 ( 2455.0666 )
        Week 10 (before end of infusion; n=25,0,0,28)
    57.308 ( 13.3588 )
    ( )
    ( )
    1992.756 ( 2968.1285 )
        Week 10 (8 hours post-dose; n=25,0,0,28)
    177.323 ( 554.8131 )
    ( )
    ( )
    2012.384 ( 2795.8138 )
        Week 10 (post 24 hours; n=24,0,0,28)
    222.980 ( 772.9408 )
    ( )
    ( )
    1849.835 ( 2671.9526 )
        Week 11 (n=25,0,0,26)
    59.441 ( 13.6892 )
    ( )
    ( )
    1743.100 ( 2621.0687 )
        Week 12 (n=25,0,0,28)
    63.416 ( 18.4243 )
    ( )
    ( )
    1710.966 ( 2838.0975 )
    Notes
    [4] - Due to change in total NGF assay during study course, participants from this arm are not analysed.
    [5] - Due to change in total NGF assay during study course, participants from this arm are not analysed.
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) to MEDI7352

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    End point title
    		 Number of Participants With Positive Anti-Drug Antibodies (ADA) to MEDI7352
    End point description
    Number of participants with positive ADA to MEDI7352 are reported. Treatment-induced ADA positive is defined as ADA negative at baseline and positive at least 1 post-baseline assessment. Treatment-boosted ADA positive is defined as ADA positive at baseline with pre-existing titer boosted by 4-fold or greater during the study period. Persistent positive is defined as ADA negative at baseline and positive at least 2 post-baseline assessments (with >= 16 weeks between first and last positive) or ADA positive at last post-baseline assessment. Transiently positive is defined as ADA negative at baseline and at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received. Here, number of participants analyzed (N) denotes those participants who had adequate ADA sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose at baseline (Day -45 to -1) and Study Weeks 2, 4, 8, 10, 12, and 18 (follow-up)
    End point values
    		 Placebo MEDl7352 Low Dose MEDl7352 Medium Dose MEDI7352 High Dose
    Number of subjects analysed
    53
    4
    14
    35
    Units: Participants
        Treatment-induced ADA
    0
    3
    7
    28
        Treatment-boosted ADA
    0
    0
    1
    1
        Persistently positive ADA
    0
    3
    6
    26
        Transiently positive ADA
    0
    0
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through 20.42 weeks (maximum observed duration)
    Adverse event reporting additional description
    Safety population included all participants who received at least 1 dose of any double-blind study drug and were analyzed according to the treatment they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received intravenous (IV) placebo infusion matched to MEDl7352 during 12-week treatment period.

    Reporting group title
    MEDl7352 Medium Dose
    Reporting group description
    		 Participants received IV MEDl7352 during 12-week treatment period.

    Reporting group title
    MEDI7352 High Dose
    Reporting group description
    		 Participants received IV MEDl7352 during 12-week treatment period.

    Reporting group title
    MEDl7352 Low Dose
    Reporting group description
    		 Participants received IV MEDl7352 during 12-week treatment period.

    Serious adverse events
    		 Placebo MEDl7352 Medium Dose MEDI7352 High Dose MEDl7352 Low Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Infections and infestations
    Lung abscess
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo MEDl7352 Medium Dose MEDI7352 High Dose MEDl7352 Low Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 54 (55.56%)
    10 / 14 (71.43%)
    23 / 35 (65.71%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Orthostatic hypertension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Catheter site swelling
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Facial pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gravitational oedema
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Psychiatric disorders
    Bruxism
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood glucose decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urine analysis abnormal
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Protein urine present
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lymph node palpable
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Coagulation test abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Bacterial test positive
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Repetitive strain injury
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail injury
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Contusion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 54 (9.26%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    3 / 4 (75.00%)
         occurrences all number
    9
    2
    1
    24
    Allodynia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    4
    Burning sensation
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diabetic neuropathy
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Sensory disturbance
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Eye haemorrhage
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Mouth ulceration
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Change of bowel habit
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    5 / 54 (9.26%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Melaena
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Lichenification
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Renal and urinary disorders
    Urinary tract inflammation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    3
    1
    Muscle twitching
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    0
    1
    Soft tissue mass
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pain in jaw
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 14 (0.00%)
    4 / 35 (11.43%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    5
    0
    Herpes simplex
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Acute sinusitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 54 (20.37%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 4 (0.00%)
         occurrences all number
    11
    0
    3
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2019
    Added assessments of strength (dorsiflexion) and deep tendon reflexes (knee and ankle). Changed terminology from “cohort” to “stage”. Added contraception guidance as an appendix. Modified the exclusion criteria to clarify that bilateral ankle radiographs were required at screening only if the participant had clinically significant sensory impairment. Modified the exclusion criteria to exclude participants with hemoglobin A1C (HbA1C) greater than 8.5% (formerly 8.0%). Specified that QuantiFERON tuberculosis (TB) testing was to be performed for all participants. Added a provision that, if necessary, the randomisation transaction in interactive web response system (IWRS) could be performed on Day -1. To avoid undue pressure on the participants, removed language that instructed the investigator to make every reasonable attempt to keep participants in the study. Added option for the sponsor to provide sterile water for injection and sodium chloride 0.9% solution for infusion if the site was unable to supply these. Noted that investigational product (IP) kit/code numbers were not to be recorded in the electronic case report form (eCRF). Removed the requirement that smoking habits were to remain unchanged for the duration of the study. Clarified that screening and Day 1 blood pressure assessments taken to assess orthostasis were to be measured in a supine (not sitting) position prior to the standing assessments. Clarified that urine pregnancy tests were to be performed in all women who were not surgically sterile. Specified that the sleep biosensor was to be worn on the nondominant wrist. Revised the list of sleep endpoints that the biosensor was capable of recording and analysing. Removed references to a clinical monitoring plan. Removed “Medimmune” from the sponsor name. Corrected typographical errors.
    21 Feb 2020
    Modified exclusion criteria to clarify that participants with a documented or suspected history of excessive alcohol usage or recreational drug usage should be evaluated at screening using appropriate quantitative or semi-quantitative methodologies according to local standards of accepted medical or psychiatric practice. Modified all instances of physical examinations to include physical and neurological examinations. Clarified that if the infusion was slowed or interrupted, the total infusion time should not exceed 4 hours at room temperature. Clarified that the timing of ECGs on Day 1 was relative to the start of IP administration. Added C-reactive protein to the serum chemistry tests to be performed. Modified the modified intent-to-treat population to include all randomised participants who received at least 1 dose of double-blind study medication and had at least 1 post-baseline (BL) NRS assessment.
    01 Oct 2020
    Modified doses used in Stage 3 of the study to include 10, 50, 150 and 450 μg/mL. Clarified the timing windows, namely for all vital signs, pharmacokinetic (PK), pharmacodynamic (PD), exploratory soluble biomarker sampling. Updated Clinical Experience from the most recent data safety cut-off of 23 April 2020. Modified the description of when participants in Stage 3 were to be randomly assigned to treatment of MEDI7352 or placebo. Modified the study design figure to include 10, 50, 150, and 450 μg/mL dose levels. Clarified the New York Heart Association (NYHA) exclusion criteria. Updated the number of study sites. Updated the study duration timing. Clarified who was to be included as an early terminated participant. Removed the futility analysis and clarified the naming of the Interim Analysis Review Committee to review the data for the interim analysis.
    04 Dec 2020
    Added a fourth stage to the study and updated the number of participants to be included in each stage. Modified doses used in Stage 2 to 4 of the study. Clarified the timing windows, namely for all vital signs, PK, PD, exploratory soluble biomarker sampling. Updated Clinical Experience from the most recent data safety cut-off of 23 April 2020. Modified the description about the timing of randomization before Stage 3. Modified the study design figure to include the appropriate dosing during the 4 stages of the study. Modified the sample size description and number of participants needed in the study. Updated the efficacy analysis to include a supplementary analysis using an adaptive MCP-Mod method. Updated when participants could be replaced to the third and fourth stages of the study. Clarified the NYHA exclusion criteria. Updated the number of study sites. Updated the study duration. Clarified who was to be defined as an early terminated participant.
    26 Oct 2021
    Updated clinical experience with data from the completed and ongoing clinical studies as of 01 June 2021 in line with the updated investigator’s brochure (Edition 6, dated 13 October 2021). Added text to exclusion criteria #11 to indicate that bilateral radiographs taken to evaluate osteoarthritis severity and exclude neuropathic arthropathy should include feet as well as ankles. Modified the definition of hypertension in exclusion criteria #27. Modified the HbA1C limit in exclusion criteria #29, from 8.5% to 10.0%. Evaluation of a cartilage degradation marker, urine C-terminal cross-linked telopeptide of type II collagen, was added. Corresponding changes were made to the exploratory endpoint describing soluble and genomic biomarkers to include this marker, with additional changes to the schedule of events and to text describing procedures at the appropriate visits. Adverse events of special interest (AESI) were added to align AESIs across studies per participant safety recommendations.
    13 Apr 2022
    Broadened electrocardiogram (ECG) language to allow paper ECGs as an alternative to digital ECGs. Clarified that the principal investigator’s assessment of each ECG was to be recorded in the eCRF as normal, abnormal and clinically significant, or abnormal and not clinically significant. Clarified that urine samples for CTX-II biomarkers should only be collected from participants who had a baseline sample collected at the screening visit. Clarified the details relating to the interim analysis after completion of stage 3. Provided additional details of vital signs capture, particularly with regard to the use of a supine or sitting position.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Mar 2020
    Study halted temporarily due to COVID-19 pandemic
    11 Jan 2021

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Dose-response relationship outcome was not evaluated by MCP-MOD because of insufficient number of doses. Study was prematurely terminated due to longer enrolment time. PK data analysed using population PK method; reported as separate report.
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