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    Clinical Trial Results:
    A phase 2/3 placebo-controlled, double-blind, randomized, trial of Diclofenac Gel AMZ001 3.06 % for the treatment of knee osteoarthritis symptoms

    Summary
    EudraCT number
    2018-001934-16
    Trial protocol
    DK   CZ  
    Global end of trial date
    09 Jul 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jul 2020
    First version publication date
    27 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AMZ001-006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03691844
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amzell B.V.
    Sponsor organisation address
    Siriusdreef 41, Hoofddorp, Netherlands, 2132 WT
    Public contact
    Clinical Development, Amzell B.V., amzell-disclosure@amzell.com
    Scientific contact
    Clinical Development, Amzell B.V., amzell-disclosure@amzell.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
    20 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the change in pain intensity, in terms of the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain score of the target knee at week 4.
    Protection of trial subjects
    The Subjects experiencing adverse events were followed-up by the investigator until resolution or until the medical condition of the subject was stable.
    Background therapy
    The trial allowed paracetamol/acetaminophen tablets 500 mg up to 4 g per day to be used as analgesic rescue medication in case of intolerable pain during the trial.
    Evidence for comparator
    The trial used a Placebo gel as a comparator in a double-blind setting and an exploratory comparator arm with Voltaren gel 1% as a single-blind component.
    Actual start date of recruitment
    04 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
    United States: 110
    Country: Number of subjects enrolled
    Czech Republic: 231
    Country: Number of subjects enrolled
    Denmark: 103
    Worldwide total number of subjects
    444
    EEA total number of subjects
    334
    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)
    216
    From 65 to 84 years
    227
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were recruited from seven trial sites in Denmark (1 site), Czech Republic (3 sites) and the USA (3 sites).

    Pre-assignment
    Screening details
    A total of 801 subjects were screened for the trial. 319 subjects failed to meet the eligibility criteria, 38 subjects discontinued before randomisation.

    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, Assessor
    Blinding implementation details
    All double-blind Investigational products were indistinguishable in appearance with respect to the container, the label, as well as the gel appearance, smell and texture, and neither subjects, investigator, or staff working on the trial were aware of treatment allocation to the double-blind treatment groups. In the single-blind arm with Voltaren gel four times a day (QID), Gel tubes were masked to fully cover any branding information.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AMZ001 twice daily (BID)
    Arm description
    AMZ001 gel twice daily
    Arm type
    Experimental

    Investigational medicinal product name
    AMZ001 gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Gel application

    Arm title
    AMZ001 once daily (QD)
    Arm description
    AMZ001 gel once daily, Placebo gel once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    AMZ001 gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Gel application

    Arm title
    Placebo Twice daily (BID)
    Arm description
    Placebo gel twice daily.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo Gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Placebo gel application.

    Arm title
    Voltaren Gel four times a day (QID)
    Arm description
    Voltaren gel 1% applied 4 times a day.
    Arm type
    Active comparator

    Investigational medicinal product name
    Voltaren gel 1% QID
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Voltaren gel 1% 4 times a day.

    Number of subjects in period 1
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID) Voltaren Gel four times a day (QID)
    Started
    121
    121
    121
    81
    Completed
    114
    109
    108
    70
    Not completed
    7
    12
    13
    11
         Protocol deviation
    -
    -
    2
    1
         Physician decision
    -
    1
    -
    -
         Lack of efficacy
    1
    2
    2
    1
         Adverse event, non-fatal
    3
    8
    7
    5
         Consent withdrawn by subject
    1
    1
    2
    2
         Lost to follow-up
    2
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AMZ001 twice daily (BID)
    Reporting group description
    AMZ001 gel twice daily

    Reporting group title
    AMZ001 once daily (QD)
    Reporting group description
    AMZ001 gel once daily, Placebo gel once daily.

    Reporting group title
    Placebo Twice daily (BID)
    Reporting group description
    Placebo gel twice daily.

    Reporting group title
    Voltaren Gel four times a day (QID)
    Reporting group description
    Voltaren gel 1% applied 4 times a day.

    Reporting group values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID) Voltaren Gel four times a day (QID) Total
    Number of subjects
    121 121 121 81 444
    Age categorical
    Units: Subjects
        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)
    60 55 62 39 216
        From 65-84 years
    61 66 59 41 227
        85 years and over
    0 0 0 1 1
    Gender categorical
    Units: Subjects
        Female
    83 83 77 54 297
        Male
    38 38 44 27 147

    End points

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    End points reporting groups
    Reporting group title
    AMZ001 twice daily (BID)
    Reporting group description
    AMZ001 gel twice daily

    Reporting group title
    AMZ001 once daily (QD)
    Reporting group description
    AMZ001 gel once daily, Placebo gel once daily.

    Reporting group title
    Placebo Twice daily (BID)
    Reporting group description
    Placebo gel twice daily.

    Reporting group title
    Voltaren Gel four times a day (QID)
    Reporting group description
    Voltaren gel 1% applied 4 times a day.

    Primary: WOMAC pain Sub-score

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    End point title
    WOMAC pain Sub-score [1]
    End point description
    Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 [no pain]-50 [extreme pain]) on target knee (double-blind treatment group only). The WOMAC pain sub-score was normalised to a 0-100 point scale for data analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -26.49 (-29.6 to -23.38)
    -27.33 (-30.5 to -24.17)
    -22.73 (-25.9 to -19.55)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0969
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.21
         upper limit
    0.68
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.044
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.09
         upper limit
    -0.12
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7098
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    5.28

    Secondary: WOMAC Total Score

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    End point title
    WOMAC Total Score [2]
    End point description
    Change from baseline in WOMAC total score (double-blind treatment group only). The WOMAC total score was normalised to a 0-100 point scale for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale.
        least squares mean (confidence interval 95%)
    -24.15 (-26.95 to -21.34)
    -23.32 (-26.16 to -20.47)
    -20.57 (-23.42 to -17.72)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0789
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.58
         upper limit
    0.42
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1802
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.78
         upper limit
    1.28
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6837
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.83
         upper limit
    3.17

    Secondary: WOMAC function score

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    End point title
    WOMAC function score [3]
    End point description
    Change from baseline in WOMAC function score (double-blind treatment group only). The WOMAC function score was normalised to a 0-100 point scale for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4. Change from baseline in WOMAC function csore (double-blind treatment group only).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -23.43 (-26.29 to -20.58)
    -22.30 (-25.19 to -19.40)
    -19.94 (-22.84 to -17.04)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    Placebo Twice daily (BID) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0921
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.57
         upper limit
    0.57
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2593
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.46
         upper limit
    1.74
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5834
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.21
         upper limit
    2.93

    Secondary: WOMAC stiffness

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    End point title
    WOMAC stiffness [4]
    End point description
    Change from baseline in WOMAC stiffness score (double-blind treatment group only). The WOMAC stiffness score was normalised to a 0-100 point scale for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale.
        least squares mean (confidence interval 95%)
    -23.17 (-26.42 to -19.93)
    -23.35 (-26.66 to -20.05)
    -20.65 (-23.96 to -17.34)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2854
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.16
         upper limit
    2.11
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2567
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.38
         upper limit
    1.97
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9394
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.45
         upper limit
    4.81

    Secondary: WOMAC pain weight-bearing score

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    End point title
    WOMAC pain weight-bearing score [5]
    End point description
    Changes from baseline in the WOMAC pain weight-bearing score (questions 1, 2 and 5) (double-blind treatment groups only). The WOMAC pain weight-bearing score was normalised to a 0-100 point scale for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -27.03 (-30.36 to -23.70)
    -27.68 (-31.07 to -24.30)
    -22.65 (-26.04 to -19.25)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.071
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -4.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.14
         upper limit
    0.38
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0396
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -5.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.83
         upper limit
    -0.24
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7877
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    5.4

    Secondary: WOMAC pain non-weight-bearing score

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    End point title
    WOMAC pain non-weight-bearing score [6]
    End point description
    Changes from baseline in the WOMAC pain non-weight-bearing score (questions 1, 2 and 5) (double-blind treatment groups only). The WOMAC pain non-weight-bearing score was normalised to a 0-100 point scale for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -25.65 (-28.87 to -22.44)
    -26.89 (-30.17 to -23.61)
    -22.93 (-26.22 to -19.65)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    Placebo Twice daily (BID) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.246
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.32
         upper limit
    1.88
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0944
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.6
         upper limit
    0.68
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5961
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.35
         upper limit
    5.83

    Secondary: ICOAP total score

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    End point title
    ICOAP total score [7]
    End point description
    Change from baseline in total Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 [no pain]- 4 [extreme pain]) (double-blind treatment group only). ICOAP scores were normalized to a 0-100-point scale for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -20.62 (-23.40 to -17.84)
    -18.87 (-21.72 to -16.02)
    -17.98 (-20.83 to -15.13)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1941
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.62
         upper limit
    1.35
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.664
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.92
         upper limit
    3.14
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3896
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.73
         upper limit
    2.24

    Secondary: ICOAP constant pain score

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    End point title
    ICOAP constant pain score [8]
    End point description
    Change from baseline in total Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 [no pain]- 4 [extreme pain]) (double-blind treatment group only) .ICOAP scores were normalized to a 0-100-point scale for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -20.82 (-23.91 to -17.73)
    -19.01 (-22.18 to -15.83)
    -18.37 (-21.54 to -15.19)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2784
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.88
         upper limit
    1.98
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7808
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.13
         upper limit
    3.86
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4222
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.25
         upper limit
    2.62

    Secondary: ICOAP intermittent pain score

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    End point title
    ICOAP intermittent pain score [9]
    End point description
    Change from baseline in total Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 [no pain]- 4 [extreme pain]) (double-blind treatment group only) .ICOAP scores were normalized to a 0-100-point scale for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, week 4.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -20.18 (-23.19 to -17.17)
    -19.00 (-22.09 to -15.92)
    -17.99 (-21.08 to -14.90)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3202
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.51
         upper limit
    2.13
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6496
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.38
         upper limit
    3.36
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5926
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.49
         upper limit
    3.14

    Secondary: Chair-stand test

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    End point title
    Chair-stand test [10]
    End point description
    Physical function assessed by the Chair-stand test. Change from baseline in physical function assessed by the chair-stand test.
    End point type
    Secondary
    End point timeframe
    baseline, week 4
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: number of repetitions
        least squares mean (confidence interval 95%)
    2.41 (1.98 to 2.83)
    2.30 (1.87 to 2.72)
    2.37 (1.94 to 2.80)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9051
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.57
         upper limit
    0.64
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8049
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.53
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7126
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.49
         upper limit
    0.71

    Secondary: OMERACT-OARSI responder rate

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    End point title
    OMERACT-OARSI responder rate [11]
    End point description
    OMERACT-OARSI (Outcome Measures in Rheumatology- Osteoarthritis Research Society International) responder rate (double-blind treatment group only)
    End point type
    Secondary
    End point timeframe
    Week 4
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    115
    109
    109
    Units: none
        number (confidence interval 95%)
    0.765 (0.679 to 0.834)
    0.826 (0.743 to 0.886)
    0.725 (0.634 to 0.800)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4876
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    1.238
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.678
         upper limit
    2.26
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0763
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.799
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.94
         upper limit
    3.443
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2642
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.688
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.357
         upper limit
    1.326

    Secondary: Total dose of rescue medication

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    End point title
    Total dose of rescue medication [12]
    End point description
    Total dose of rescue medication calculated as the average gram use/day, based on pill counts (double-blind treatment group only).
    End point type
    Secondary
    End point timeframe
    week 1 through week 4
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    120
    120
    120
    Units: g/day
        least squares mean (confidence interval 95%)
    0.27 (0.19 to 0.36)
    0.31 (0.22 to 0.40)
    0.30 (0.21 to 0.39)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6432
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.1
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9351
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.13
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5859
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.09

    Secondary: Time between baseline and first use of rescue medication

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    End point title
    Time between baseline and first use of rescue medication [13]
    End point description
    Time between baseline and first use of rescue medication (double-blind treatment group only)
    End point type
    Secondary
    End point timeframe
    week 1 through week 4
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    119
    120
    120
    Units: days
        median (confidence interval 95%)
    17 (7 to 24)
    9 (5 to 15)
    10 (4 to 17)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1248
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.07
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4136
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.2
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4618
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.22

    Secondary: Impact of Osteoarthritis on daily living (PGA score)

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    End point title
    Impact of Osteoarthritis on daily living (PGA score) [14]
    End point description
    Changes from baseline in the impact of osteoarthritis on daily living as assessed by the Patient Global Assessment (PGA) score (0 [none] - 10 [extreme]) (double-blind treatment group only)
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    119
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -2.29 (-2.63 to -1.94)
    -2.31 (-2.66 to -1.96)
    -1.68 (-2.03 to -1.32)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0162
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.11
         upper limit
    -0.11
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0134
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    -0.13
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9321
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    0.52

    Secondary: WPAI % time missed

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    End point title
    WPAI % time missed [15]
    End point description
    Changes from baseline in the percentage of work time missed due to health, assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteesism, work productivity loss, and activity impairment). It was determined only for subjects currently employed (doubleblind treatment group only)
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    45
    41
    39
    Units: percentage time
        least squares mean (confidence interval 95%)
    0.39 (-2.73 to 3.51)
    -3.10 (-6.43 to 0.23)
    1.58 (-2.01 to 5.16)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6228
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.95
         upper limit
    3.57
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0612
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.58
         upper limit
    0.22
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1345
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.09
         upper limit
    8.06

    Secondary: WPAI % impairment while working

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    End point title
    WPAI % impairment while working [16]
    End point description
    Changes from baseline in the degree that health affected productivity while working expressed as a percentage, assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteesism, work productivity loss, and activity impairment). It was determined only for subjects currently employed (doubleblind treatment group only)
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    50
    47
    39
    Units: percentage
        least squares mean (confidence interval 95%)
    -13.11 (-18.71 to -7.51)
    -14.38 (-20.57 to -8.19)
    -5.28 (-12.26 to 1.70)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0876
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.81
         upper limit
    1.16
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0555
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -9.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.42
         upper limit
    0.22
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7648
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.11
         upper limit
    9.66

    Secondary: WPAI % overall work impairment

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    End point title
    WPAI % overall work impairment [17]
    End point description
    Changes from baseline in the percentage of overall work impairment due to health, assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteesism, work productivity loss, and activity impairment). It was determined only for subjects currently employed (doubleblind treatment group only).
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    43
    39
    34
    Units: percentage
        least squares mean (confidence interval 95%)
    -11.69 (-17.95 to -5.43)
    -16.93 (-23.95 to -9.91)
    -6.50 (-14.19 to 1.20)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3054
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.17
         upper limit
    4.77
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0492
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -10.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.84
         upper limit
    -0.04
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2752
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    5.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.2
         upper limit
    14.68

    Secondary: WPAI % activity impairment

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    End point title
    WPAI % activity impairment [18]
    End point description
    Changes from baseline in the the degree that health affected regular activities expressed as a percentage, assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteesism, work productivity loss, and activity impairment). It was determined only for subjects currently employed (doubleblind treatment group only).
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    119
    120
    120
    Units: percentage
        least squares mean (confidence interval 95%)
    -17.75 (-21.45 to -14.06)
    -20.41 (-24.15 to -16.68)
    -13.03 (-16.79 to -9.27)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    0.55
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0064
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.69
         upper limit
    -2.08
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3202
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.59
         upper limit
    7.92

    Secondary: EQ-5D VAS score

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    End point title
    EQ-5D VAS score [19]
    End point description
    Changes from baseline in quality of life assessed by the EQ5D (score 0 [extremely poor] -100 [great] mm on a visual analogue scale) (double-blind treatment group only)
    End point type
    Secondary
    End point timeframe
    Baseline, week 4
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    119
    120
    120
    Units: score on a scale
        least squares mean (confidence interval 95%)
    13.04 (10.13 to 15.94)
    11.76 (8.82 to 14.71)
    8.34 (5.39 to 11.28)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0264
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    8.85
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1072
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    7.6
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5459
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.86
         upper limit
    5.41

    Other pre-specified: Skin Reactions (Skin Tolerability assessment)

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    End point title
    Skin Reactions (Skin Tolerability assessment)
    End point description
    Nature, incidence and severity of skin reactions on the application site.
    End point type
    Other pre-specified
    End point timeframe
    Week 4.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID) Voltaren Gel four times a day (QID)
    Number of subjects analysed
    121
    121
    121
    81
    Units: number of events
        Normal skin; no erythema
    100
    89
    79
    68
        Questionable erythema not covering entire applicat
    14
    18
    20
    3
        Definite erythema covering entire application site
    2
    2
    10
    0
        Definite erythema and swelling or induration
    0
    0
    0
    0
        Blister formation and/or necrosis
    0
    0
    0
    1
        Not done
    0
    0
    0
    0
    No statistical analyses for this end point

    Post-hoc: WOMAC pain Sub-score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline)

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    End point title
    WOMAC pain Sub-score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline) [20]
    End point description
    Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 [no pain]-50 [extreme pain]) on target knee (sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline). The WOMAC pain sub-score was normalised to a 0-100 point scale for data analysis.
    End point type
    Post-hoc
    End point timeframe
    Baseline, week 4.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    109
    107
    106
    Units: score on a scale.
        least squares mean (confidence interval 95%)
    -28.54 (-31.87 to -25.20)
    -29.02 (-32.45 to -25.60)
    -23.18 (-26.64 to -19.72)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    Placebo Twice daily (BID) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0292
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.16
         upper limit
    -0.54
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    213
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0189
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.71
         upper limit
    -0.97
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    216
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.841
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    5.27

    Post-hoc: WOMAC Total Score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline)

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    End point title
    WOMAC Total Score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline) [21]
    End point description
    Change from baseline in WOMAC total score (sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline). The WOMAC total score was normalised to a 0-100 point scale for data analysis.
    End point type
    Post-hoc
    End point timeframe
    Baseline, week 4.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    109
    107
    106
    Units: score on a scale.
        least squares mean (confidence interval 95%)
    -25.54 (-28.54 to -22.54)
    -24.03 (-27.11 to -20.95)
    -20.61 (-23.71 to -17.51)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    215
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0252
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.24
         upper limit
    -0.62
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    213
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.125
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.79
         upper limit
    0.95
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 twice daily (BID) v AMZ001 once daily (QD)
    Number of subjects included in analysis
    216
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.4912
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.81
         upper limit
    2.79

    Post-hoc: WOMAC function score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline)

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    End point title
    WOMAC function score (subgroup with WOMAC normalized pain sub-score ≥40 at baseline) [22]
    End point description
    Change from baseline in WOMAC function score (sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline). The WOMAC total score was normalised to a 0-100 point scale for data analysis.
    End point type
    Post-hoc
    End point timeframe
    Baseline, week 4.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    109
    107
    106
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -24.69 (-27.75 to -21.64)
    -22.84 (-25.97 to -19.70)
    -19.84 (-23.00 to -16.68)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    215
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0306
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.24
         upper limit
    -0.45
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    213
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.1879
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.45
         upper limit
    1.47
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    216
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.4059
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.24
         upper limit
    2.53

    Post-hoc: WOMAC stiffness (subgroup with WOMAC normalized pain sub-score ≥40 at baseline)

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    End point title
    WOMAC stiffness (subgroup with WOMAC normalized pain sub-score ≥40 at baseline) [23]
    End point description
    Change from baseline in WOMAC stiffness score (sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline). The WOMAC stiffness score was normalised to a 0-100 point scale for data analysis.
    End point type
    Post-hoc
    End point timeframe
    Baseline, week 4.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Voltaren gel arm is an exploratory arm and exploratory endpoints results are not reported.
    End point values
    AMZ001 twice daily (BID) AMZ001 once daily (QD) Placebo Twice daily (BID)
    Number of subjects analysed
    109
    107
    106
    Units: score on scale
        least squares mean (confidence interval 95%)
    -24.08 (-27.52 to -20.64)
    -23.57 (-27.11 to -20.03)
    -20.33 (-23.89 to -16.76)
    Statistical analysis title
    AMZ001 BID treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 twice daily (BID) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    215
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.1374
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.71
         upper limit
    1.2
    Statistical analysis title
    AMZ001 QD Treatment difference vs placebo
    Statistical analysis description
    MMRM ANCOVA
    Comparison groups
    AMZ001 once daily (QD) v Placebo Twice daily (BID)
    Number of subjects included in analysis
    213
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.2058
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -3.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.27
         upper limit
    1.79
    Statistical analysis title
    AMZ001 BID Treatment difference vs AMZ001 QD
    Statistical analysis description
    MMRM ANCOVA.
    Comparison groups
    AMZ001 once daily (QD) v AMZ001 twice daily (BID)
    Number of subjects included in analysis
    216
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.8388
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.45
         upper limit
    4.43

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Informed Consent signature to safety follow-up phone call.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    AMZ001 BID
    Reporting group description
    -

    Reporting group title
    AMZ001 QD
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Voltaren Gel 1%
    Reporting group description
    -

    Serious adverse events
    AMZ001 BID AMZ001 QD Placebo Voltaren Gel 1%
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 81 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AMZ001 BID AMZ001 QD Placebo Voltaren Gel 1%
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 121 (34.71%)
    40 / 121 (33.06%)
    76 / 121 (62.81%)
    15 / 81 (18.52%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 121 (0.83%)
    8 / 121 (6.61%)
    0 / 81 (0.00%)
         occurrences all number
    3
    2
    9
    0
    General disorders and administration site conditions
    Application site dryness
         subjects affected / exposed
    18 / 121 (14.88%)
    13 / 121 (10.74%)
    16 / 121 (13.22%)
    5 / 81 (6.17%)
         occurrences all number
    18
    13
    16
    5
    Application site pruritus
         subjects affected / exposed
    5 / 121 (4.13%)
    8 / 121 (6.61%)
    6 / 121 (4.96%)
    2 / 81 (2.47%)
         occurrences all number
    5
    8
    6
    3
    Application site erythema
         subjects affected / exposed
    11 / 121 (9.09%)
    15 / 121 (12.40%)
    40 / 121 (33.06%)
    4 / 81 (4.94%)
         occurrences all number
    12
    16
    41
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 121 (4.96%)
    3 / 121 (2.48%)
    6 / 121 (4.96%)
    4 / 81 (4.94%)
         occurrences all number
    7
    3
    6
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2018
    Updates and corrections
    22 Nov 2018
    Updates

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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