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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to investigate the efficacy and safety of different intra-articular (i.a.) dosages of sprifermin in subjects with primary osteoarthritis of the knee (FORWARD)

    Summary
    EudraCT number
    2011-003059-20
    Trial protocol
    CZ   EE   DK   PL  
    Global end of trial date
    07 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    09 May 2020
    First version publication date
    09 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700692_006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01919164
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA, Darmstadt, Germany
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.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
    07 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate structural changes in cartilage thickness in the total femorotibial joint of the target knee in terms of imaging by Magnetic resonance imaging (MRI).
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Czech Republic: 170
    Country: Number of subjects enrolled
    Denmark: 125
    Country: Number of subjects enrolled
    Estonia: 72
    Country: Number of subjects enrolled
    Hong Kong: 108
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 61
    Worldwide total number of subjects
    549
    EEA total number of subjects
    429
    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)
    250
    From 65 to 84 years
    299
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Overall 1366 subjects were screened in this study. Out of which 549 subjects were randomized and received the study treatment into the study.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Subjects received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Arm title
    Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
    Arm description
    Subjects received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    AS902330
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarterial use
    Dosage and administration details
    Subjects received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3.

    Arm title
    Sprifermin (AS902330) 30 mcg- 4 Cycles
    Arm description
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    AS902330
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Arm title
    Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
    Arm description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    AS902330
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3.

    Arm title
    Sprifermin (AS902330) 100 mcg- 4 Cycles
    Arm description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    AS902330
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Number of subjects in period 1
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Started
    108
    110
    111
    110
    110
    Completed
    65
    80
    74
    82
    77
    Not completed
    43
    30
    37
    28
    33
         Consent withdrawn by subject
    13
    13
    14
    14
    9
         Disease progression
    2
    2
    1
    2
    1
         Adverse event, non-fatal
    6
    4
    9
    3
    2
         Other Un-specified
    13
    9
    8
    7
    15
         Death
    1
    -
    -
    -
    -
         Lost to follow-up
    2
    2
    2
    -
    4
         Protocol deviation
    6
    -
    3
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
    Reporting group description
    Subjects received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles Total
    Number of subjects
    108 110 111 110 110 549
    Age Categorical
    Units: Participants
        <=18 years
    0 0 0 0 0 0
        Between 18 and 65 years
    54 46 52 52 46 250
        >=65 years
    54 64 59 58 64 299
    Sex: Female, Male
    Units: Participants
        Female
    76 73 80 77 73 379
        Male
    32 37 31 33 37 170
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 1 0 0 0 2
        Not Hispanic or Latino
    107 109 111 110 110 547
        Unknown or Not Reported
    0 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0
        Asian
    21 22 23 21 23 110
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0
        Black or African American
    0 0 0 0 0 0
        White
    87 88 88 89 87 439
        More than one race
    0 0 0 0 0 0
        Unknown or Not Reported
    0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
    Reporting group description
    Subjects received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Primary: Change from Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2

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    End point title
    Change from Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2
    End point description
    The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI). Modified intent to treat (ITT) analysis set included all randomized subjects that is, only planned treatment regimen was used and who had a baseline, at least 1 post-treatment qMRI assessment available in double-blind placebo-controlled part. Here “Number of subjects analyzed” = subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Year 2 (Week 104)
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    83
    92
    83
    90
    86
    Units: millimeters
        arithmetic mean (standard deviation)
    -0.02 ( 0.07 )
    -0.01 ( 0.07 )
    0.00 ( 0.07 )
    0.02 ( 0.08 )
    0.03 ( 0.07 )
    Statistical analysis title
    Placebo vs Sprifermin 30 mcg/placebo - 2 Cycles
    Statistical analysis description
    Descriptive statistics was provided for primary endpoint.
    Comparison groups
    Placebo v Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.03
    Statistical analysis title
    Placebo vs Sprifermin 30 mcg- 4 Cycles
    Statistical analysis description
    Descriptive statistics was provided for primary endpoint.
    Comparison groups
    Placebo v Sprifermin (AS902330) 30 mcg- 4 Cycles
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.04
    Statistical analysis title
    Placebo vs Sprifermin 100 mcg/Placebo (2 cycles)
    Statistical analysis description
    Descriptive statistics was provided for primary endpoint.
    Comparison groups
    Placebo v Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.06
    Statistical analysis title
    Placebo vs Sprifermin 100 mcg- 4 Cycles
    Statistical analysis description
    Descriptive statistics was provided for primary endpoint.
    Comparison groups
    Placebo v Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    0.07

    Secondary: Changes from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, Function, Stiffness Index and Total Scores at Week 52, 78 and 104

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    End point title
    Changes from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, Function, Stiffness Index and Total Scores at Week 52, 78 and 104
    End point description
    WOMAC pain subscale consists of 5 questions (Likert Scale) relating to pain. Sum of items of pain subscale ranges from 0-11. Higher scores=worse pain. Stiffness subscale consists of 2 questions relating articular function. Sum of items of stiffness subscale ranges from 0-8. Higher scores=worse function. Physical function subscale consists of 1 question relating to physical activities. Sum of items of physical function subscale ranges from 0-68. Higher scores= worse functional limitations. Each sub-scale is directly transformed into a 0-100 scale, therefore WOMAC total score(24questions) is sum of subscale & ranges from0-100. Higher scores=worse condition. Negative value in change is indicative of improvement. “Number of subjects analyzed” = subjects evaluable for this endpoint & "n" included who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52, Week 78 and Week 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    94
    98
    89
    98
    100
    Units: score on a scale
    arithmetic mean (standard deviation)
        Total:Change at Week 52 (n=94,98,87,98,100)
    -16.42 ( 18.61 )
    -17.97 ( 16.95 )
    -12.64 ( 17.42 )
    -16.29 ( 18.35 )
    -18.29 ( 18.25 )
        Total:Change at Week 78 (n=90,94,86,94,94)
    -18.41 ( 20.43 )
    -19.34 ( 19.15 )
    -16.36 ( 20.35 )
    -18.88 ( 18.15 )
    -20.29 ( 18.49 )
        Total:Change at Week 104 (n=86,98,89,96,95)
    -22.02 ( 19.70 )
    -20.73 ( 20.22 )
    -19.44 ( 20.88 )
    -18.37 ( 18.69 )
    -22.08 ( 19.11 )
        Pain: Change at Week 52 (n=94,98,87,98,100)
    -18.51 ( 19.49 )
    -21.55 ( 18.36 )
    -15.40 ( 18.31 )
    -21.12 ( 19.73 )
    -23.34 ( 17.92 )
        Pain: Change at Week 78(n=90,94,86,94,94)
    -21.04 ( 20.81 )
    -23.00 ( 20.42 )
    -18.19 ( 21.15 )
    -23.21 ( 19.42 )
    -23.23 ( 18.41 )
        Pain: Change at Week 104(n=86,98,89,96,95)
    -25.37 ( 20.60 )
    -23.22 ( 21.42 )
    -21.42 ( 21.37 )
    -23.15 ( 18.18 )
    -26.06 ( 18.39 )
        Stiffness: Change at Week 52(n=94,98,87,98,100)
    -18.88 ( 24.72 )
    -18.52 ( 22.89 )
    -11.09 ( 21.14 )
    -16.68 ( 20.93 )
    -17.35 ( 22.16 )
        Stiffness: Change at Week 78(n=90,98,86,94,94)
    -20.44 ( 26.76 )
    -19.47 ( 25.87 )
    -14.94 ( 23.66 )
    -19.63 ( 20.38 )
    -21.44 ( 23.99 )
        Stiffness: Change at Week 104(n=86,98,89,96,95)
    -23.20 ( 25.84 )
    -20.56 ( 23.93 )
    -17.75 ( 22.74 )
    -17.76 ( 20.75 )
    -22.79 ( 23.99 )
        Function: Change at Week 52(n=94,98,87,98,100)
    -15.51 ( 19.14 )
    -16.84 ( 17.64 )
    -12.01 ( 18.04 )
    -14.80 ( 19.07 )
    -16.91 ( 19.69 )
        Function: Change at Week 78(n=90,98,86,94,94)
    -17.38 ( 21.01 )
    -18.23 ( 19.41 )
    -16.00 ( 20.82 )
    -17.51 ( 18.96 )
    -19.29 ( 19.56 )
        Function: Change at Week 104(n=86,98,89,96,95)
    -20.89 ( 20.10 )
    -20.00 ( 20.99 )
    -19.06 ( 21.52 )
    -17.03 ( 20.16 )
    -20.82 ( 20.39 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104

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    End point title
    Change from Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104
    End point description
    The 20-meter walk test is an objective test of physical function which consists of measuring the time needed for the subject to walk 20 meters at a normal pace. A stopwatch was used for time measurement. Intention-to-Treat (ITT) analysis set included all subjects randomly allocated to a treatment, based on the intention to treat “as randomized” principle. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    105
    108
    109
    107
    108
    Units: seconds
    arithmetic mean (standard deviation)
        Change at Week 12 (n=105,108,109,107,108)
    -1.2 ( 2.9 )
    -0.4 ( 4.0 )
    -0.5 ( 2.6 )
    -0.8 ( 2.2 )
    -1.1 ( 3.3 )
        Change at Week 26 (n=99,108,101,103,102)
    -1.3 ( 3.7 )
    -0.4 ( 3.9 )
    -0.3 ( 2.6 )
    -1.1 ( 2.8 )
    -1.3 ( 3.0 )
        Change at Week 38 (n=98,103,98,102,98)
    -1.1 ( 3.6 )
    -0.5 ( 3.4 )
    -0.7 ( 2.5 )
    -1.0 ( 2.9 )
    -1.4 ( 3.2 )
        Change at Week 52 (n=95,101,90,101,100)
    -1.7 ( 4.2 )
    -1.1 ( 3.6 )
    -0.7 ( 2.5 )
    -0.4 ( 7.9 )
    -1.3 ( 2.8 )
        Change at Week 64 (n=92,101,93,97,93)
    -1.8 ( 3.6 )
    -1.5 ( 4.1 )
    -0.9 ( 2.5 )
    -1.3 ( 2.6 )
    -1.6 ( 3.4 )
        Change at Week 78 (n=91,96,88,97,94)
    -1.6 ( 3.7 )
    -1.0 ( 4.0 )
    -0.8 ( 2.8 )
    -1.6 ( 3.0 )
    -1.3 ( 3.2 )
        Change at Week 90 (n=83,96,87,91,87)
    -2.1 ( 3.9 )
    -1.0 ( 3.2 )
    -1.1 ( 2.7 )
    -1.8 ( 3.1 )
    -1.7 ( 3.5 )
        Change at Week 104 (n=87,100,91,99,94)
    -1.6 ( 4.0 )
    -1.2 ( 4.1 )
    -0.8 ( 3.4 )
    -1.4 ( 2.9 )
    -1.3 ( 3.2 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104

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    End point title
    Change from Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104
    End point description
    The Patient Global Assessment is based on subject’s answer to the question “Considering all the ways your osteoarthritis of the knee has affected you during the last 48 Hours, select the number that best describes the impact of your knee osteoarthritis on your daily life”, and can take on values between 0-10 (0=None, 10=Extreme), for summaries the values are rescaled to 0-100 by multiplication with 10. Higher scores indicated worsening of condition. A negative value in change in Patient's Global Assessment is indicative of an improvement. Intention-to-Treat (ITT) analysis set included all subjects randomly allocated to a treatment, based on the intention to treat “as randomized” principle. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    104
    108
    109
    106
    107
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=104,108,109,106,107)
    -16.6 ( 23.5 )
    -13.9 ( 20.6 )
    -17.0 ( 25.0 )
    -15.0 ( 23.2 )
    -16.7 ( 22.1 )
        Change at Week 26 (n=99,108,100,103,102)
    -16.3 ( 22.3 )
    -15.1 ( 22.7 )
    -17.7 ( 25.3 )
    -18.7 ( 22.4 )
    -19.1 ( 24.1 )
        Change at Week 38 (n=98,103,97,102,98)
    -18.9 ( 26.2 )
    -17.2 ( 22.5 )
    -19.2 ( 24.9 )
    -20.5 ( 24.3 )
    -18.4 ( 25.1 )
        Change at Week 52 (n=95,100,88,101,100)
    -19.6 ( 25.8 )
    -20.9 ( 21.2 )
    -18.0 ( 23.9 )
    -19.5 ( 25.2 )
    -21.6 ( 24.0 )
        Change at Week 64 (n=92,101,93,97,93)
    -22.7 ( 24.6 )
    -21.7 ( 21.9 )
    -22.3 ( 23.0 )
    -21.6 ( 25.8 )
    -21.3 ( 24.6 )
        Change at Week 78 (n=91,96,88,97,93)
    -22.7 ( 26.5 )
    -21.5 ( 24.1 )
    -23.1 ( 25.7 )
    -22.0 ( 25.4 )
    -24.2 ( 24.1 )
        Change at Week 90 (n=83,97,87,91,87)
    -25.8 ( 25.6 )
    -22.3 ( 24.5 )
    -21.7 ( 24.8 )
    -21.1 ( 26.3 )
    -26.2 ( 24.9 )
        Change at Week 104 (n=87,100,91,99,95)
    -27.5 ( 25.0 )
    -23.0 ( 22.3 )
    -23.8 ( 24.9 )
    -22.1 ( 25.6 )
    -25.8 ( 22.8 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Minimal Joint Space Width (mJSW) in the Medial and Lateral Compartments as Evaluated by X-ray at Week 52 and 104

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    End point title
    Change from Baseline in Minimal Joint Space Width (mJSW) in the Medial and Lateral Compartments as Evaluated by X-ray at Week 52 and 104
    End point description
    Change in joint space narrowing was visualized with the “fixed flexion” knee radiograph. Determination of joint space narrowing by X-ray is considered to be a semi-quantitative method for assessment of progression of knee osteoarthritis (OA). X-rays of both the target knee and the contralateral knee were performed. X-rays were read centrally. X-ray images were used to measure mJSW in the medial femorotibial and lateral femorotibial compartments and to determine the subject's baseline Kellgren-Lawrence grades (KLG). Intention-to-Treat (ITT) analysis set included all subjects randomly allocated to a treatment, based on the intention to treat “as randomized” principle. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52 and 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    95
    101
    95
    100
    101
    Units: millimeter
    arithmetic mean (standard deviation)
        Medial: at Week 52 (n=95,97,89,100,101)
    -0.10 ( 0.48 )
    -0.05 ( 0.53 )
    -0.04 ( 0.43 )
    0.02 ( 0.55 )
    -0.04 ( 0.57 )
        Medial: at Week 104 (n=90,101,95,98,95)
    -0.11 ( 0.59 )
    -0.09 ( 0.73 )
    0.03 ( 0.52 )
    -0.05 ( 0.66 )
    -0.07 ( 0.86 )
        Lateral: at Week 52 (n=95,97,89,100,101)
    0.07 ( 0.46 )
    -0.03 ( 0.62 )
    0.16 ( 0.54 )
    0.10 ( 0.37 )
    0.14 ( 0.43 )
        Lateral: at Week 104 (n=90,101,95,98,95)
    -0.07 ( 0.49 )
    -0.03 ( 0.64 )
    0.01 ( 0.65 )
    0.19 ( 0.49 )
    0.19 ( 0.49 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cartilage Thickness in the Medial and Lateral Compartments as well as in the Total Femorotibial Joint at 26, 52, 78 and 104

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    End point title
    Change from Baseline in Cartilage Thickness in the Medial and Lateral Compartments as well as in the Total Femorotibial Joint at 26, 52, 78 and 104
    End point description
    The change in cartilage thickness at Week 26, 52, 78 and 104 was calculated based on quantitative magnetic resonance imaging (qMRI). Modified intent to treat (ITT) analysis set included all randomized subjects that is, only planned treatment regimen was used and who had a baseline, at least 1 post-treatment qMRI assessment available in double-blind placebo-controlled part. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, 52, 78 and 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    94
    97
    97
    96
    99
    Units: millimeter
    arithmetic mean (standard deviation)
        Medial: at Week 26 (n=93,97,95,95,99)
    0.00 ( 0.06 )
    0.00 ( 0.06 )
    -0.01 ( 0.06 )
    0.01 ( 0.05 )
    0.01 ( 0.06 )
        Medial: at Week 52 (n=91,93,81,94,93)
    -0.01 ( 0.06 )
    -0.01 ( 0.07 )
    -0.01 ( 0.06 )
    0.00 ( 0.07 )
    0.01 ( 0.06 )
        Medial: at Week 78 (n=84,91,84,90,89)
    -0.01 ( 0.07 )
    -0.01 ( 0.07 )
    0.01 ( 0.06 )
    0.01 ( 0.10 )
    0.03 ( 0.08 )
        Medial: at Week 104 (n=83,92,83,90,86)
    -0.03 ( 0.12 )
    -0.02 ( 0.10 )
    -0.01 ( 0.08 )
    0.00 ( 0.11 )
    0.02 ( 0.08 )
        Lateral: at Week 26 (n=94,97,97,96,99)
    -0.01 ( 0.05 )
    0.00 ( 0.05 )
    0.00 ( 0.06 )
    0.02 ( 0.05 )
    0.02 ( 0.05 )
        Lateral: at Week 52 (n=92,93,83,95,93)
    -0.01 ( 0.05 )
    -0.01 ( 0.07 )
    0.00 ( 0.05 )
    0.02 ( 0.06 )
    0.02 ( 0.05 )
        Lateral: at Week 78 (n=85,91,85,91,89)
    0.00 ( 0.05 )
    0.01 ( 0.06 )
    0.01 ( 0.08 )
    0.03 ( 0.07 )
    0.03 ( 0.06 )
        Lateral: at Week 104 (n=83,92,85,91,86)
    -0.01 ( 0.05 )
    -0.01 ( 0.07 )
    0.00 ( 0.09 )
    0.04 ( 0.07 )
    0.04 ( 0.06 )
        Total: at Week 26 (n=93,97,95,95,99)
    -0.01 ( 0.05 )
    0.00 ( 0.04 )
    0.00 ( 0.05 )
    0.01 ( 0.04 )
    0.01 ( 0.05 )
        Total: at Week 52 (n=91,93,81,94,93)
    -0.01 ( 0.05 )
    -0.01 ( 0.06 )
    0.00 ( 0.05 )
    0.01 ( 0.06 )
    0.01 ( 0.05 )
        Total: Change at Week 78 (n=84,91,84,90,89)
    -0.01 ( 0.05 )
    0.00 ( 0.06 )
    0.06 ( 0.06 )
    0.02 ( 0.07 )
    0.03 ( 0.06 )
        Total: Change at Week 104 (n=83,92,83,96,86)
    -0.02 ( 0.07 )
    -0.01 ( 0.07 )
    0.00 ( 0.07 )
    0.02 ( 0.08 )
    0.03 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cartilage-Volume in the Medial and Lateral Compartments as well as in the Total Femorotibial Joint at Week 26, 52, 78 and 104

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    End point title
    Change from Baseline in Cartilage-Volume in the Medial and Lateral Compartments as well as in the Total Femorotibial Joint at Week 26, 52, 78 and 104
    End point description
    The change in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint at Week 26, 52, 78 and 104 was calculated based on qMRI.Modified ITT analysis set was used. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, 52, 78 and 104
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    96
    101
    98
    99
    99
    Units: microliter
    arithmetic mean (standard deviation)
        Medial: at Week 26 (n=93,97,95,95,99)
    0.0 ( 112.2 )
    1.7 ( 110.8 )
    -3.2 ( 99.5 )
    16.7 ( 89.8 )
    16.5 ( 114.2 )
        Medial: at Week 52 (n=91,93,81,94,93)
    -10.2 ( 100.7 )
    -2.9 ( 127.1 )
    -7.0 ( 103.7 )
    3.6 ( 127.5 )
    16.5 ( 110.6 )
        Medial: at Week 78 (n=84,91,84,90,89)
    -8.9 ( 125.3 )
    -7.0 ( 153.7 )
    23.6 ( 109.3 )
    33.2 ( 177.0 )
    53.9 ( 147.3 )
        Medial: at Week 104 (n=83,92,83,90,86)
    -41.0 ( 192.1 )
    -21.4 ( 198.3 )
    3.6 ( 123.9 )
    19.5 ( 202.3 )
    48.6 ( 150.7 )
        Lateral: at Week 26 (n=94,97,97,96,99)
    -12.8 ( 84.4 )
    0.8 ( 82.0 )
    1.5 ( 102.3 )
    31.3 ( 87.7 )
    25.1 ( 85.8 )
        Lateral: at Week 52 (n=92,93,83,95,93)
    -12.7 ( 94.0 )
    -17.5 ( 141.1 )
    2.7 ( 98.2 )
    32.4 ( 107.5 )
    28.1 ( 87.3 )
        Lateral: at Week 78 (n=85,91,85,91,89)
    -1.8 ( 89.7 )
    13.9 ( 113.6 )
    21.6 ( 129.0 )
    55.9 ( 123.1 )
    55.2 ( 101.6 )
        Lateral: at Week 104 (n=83,92,85,91,86)
    -14.5 ( 87.2 )
    -6.8 ( 144.9 )
    7.2 ( 134.8 )
    75.5 ( 111.8 )
    67.9 ( 112.5 )
        Total: at Week 26 (n=93,97,95,95,99)
    -13.0 ( 163.2 )
    2.5 ( 147.0 )
    -2.9 ( 161.8 )
    48.4 ( 150.9 )
    41.5 ( 166.6 )
        Total: at Week 52 (n=91,93,81,94,93)
    -23.7 ( 155.7 )
    -20.4 ( 217.6 )
    -5.5 ( 169.0 )
    36.2 ( 203.1 )
    44.7 ( 163.2 )
        Total: Change at Week 78 (n=84,91,84,90,89)
    -10.3 ( 176.8 )
    6.9 ( 228.1 )
    44.8 ( 195.3 )
    89.9 ( 272.6 )
    109.1 ( 219.1 )
        Total: Change at Week 104 (n=83,92,83,90,86)
    -55.5 ( 239.5 )
    -28.2 ( 275.7 )
    9.5 ( 205.7 )
    96.6 ( 271.1 )
    116.5 ( 233.5 )
    No statistical analyses for this end point

    Secondary: Synovial Fluid Levels of sprifermin/FGF-18

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    End point title
    Synovial Fluid Levels of sprifermin/FGF-18
    End point description
    Levels of sprifermin/FGF-18 in synovial fluid were measured to provide a first estimate of the residence time of sprifermin in the synovial fluid. Safety analysis set included all subjects who received at least 1 dose of study treatment. Arm assignments for subjects in Safety Set were based on actual treatment received. Here “Number of subjects analyzed” = subjects evaluable for this outcome measure and "n" included those who were evaluable at specified timepoints. "n" also signifies subjects evaluable at specified time points and "99999" signifies "NA".
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 0 thereafter 2 hours post-dose at Week 1, 2 and 3 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    3
    20
    22
    25
    27
    Units: picogram/milliliter
    median (full range (min-max))
        Week 0; Cycle 1 (n=5,5,5,8,0)
    99999 (99999 to 99999)
    56876.4 (5843.8 to 86068.0)
    1006.5 (206.6 to 34439.4)
    1386.1 (260.4 to 36766.4)
    5896.4 (631.3 to 238780.1)
        Week 1; Cycle 1 (n=5,7,10,16,2)
    622.1 (156.0 to 1088.2)
    3628.3 (229.9 to 37140.5)
    1493.2 (214.2 to 110515.4)
    359.8 (151.2 to 37014.8)
    1062.3 (156.7 to 840122.2)
        Week 2; Cycle 1 (n=10,6,12,16,0)
    99999 (99999 to 99999)
    3150.9 (189.1 to 33378.5)
    4167.0 (460.3 to 8857.1)
    467.9 (150.7 to 108866.0)
    258.2 (171.9 to 48066.3)
        Week 0; Cycle 3 (n=20,15,9,13,3)
    463.7 (223.8 to 5386.5)
    8019.3 (279.2 to 358231.4)
    9443.4 (505.7 to 271320.6)
    16901.2 (461.0 to 273247.0)
    20753.0 (4119.1 to 303440.5)
        Week 1; Cycle 3 (n=14,11,16,22,0)
    99999 (99999 to 99999)
    8607.6 (276.7 to 147723.9)
    4605.1 (337.2 to 358029.6)
    3908.8 (177.5 to 86823.9)
    10160.0 (165.5 to 375638.7)
        Week 2; Cycle 3 (n=15,15,25,25,1)
    260.9 (260.9 to 260.9)
    9592.2 (1277.1 to 35615.5)
    9422.2 (409.3 to 353582.4)
    1801.0 (171.9 to 77338.9)
    4161.7 (151.1 to 213692.3)
        Week 0; Cycle 2 (n=0,10,1,13,1)
    202.5 (202.5 to 202.5)
    99999 (99999 to 99999)
    7039.1 (309.8 to 1108182.4)
    308.2 (308.2 to 308.2)
    32360.2 (559.9 to 683691.9)
        Week 1; Cycle 2 (n=0,17,0,16,0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    14756.3 (904.6 to 359059.2)
    99999 (99999 to 99999)
    7036.9 (159.9 to 82301.6)
        Week 2; Cycle 2 (n=0,16,0,18,0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    6408.3 (154.4 to 220629.5)
    99999 (99999 to 99999)
    1146.7 (156.1 to 42598.5)
        Week 0; Cycle 4 (n=0,17,0,16,0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12458.4 (224.6 to 163129.3)
    99999 (99999 to 99999)
    22132.1 (215.7 to 897758.2)
        Week 1; Cycle 4 (n=0,18,1,22,1)
    215.3 (215.3 to 215.3)
    99999 (99999 to 99999)
    9602.7 (178.6 to 45631.9)
    2285.2 (2285.2 to 2285.2)
    11468.3 (157.5 to 142318.7)
        Week 2; Cycle 4 (n=0,22,2,27,1)
    10670.0 (10670.0 to 10670.0)
    99999 (99999 to 99999)
    7103.8 (196.8 to 384511.5)
    331.1 (168.4 to 493.7)
    8026.4 (179.7 to 272804.6)
    No statistical analyses for this end point

    Secondary: Serum Levels of Sprifermin/FGF-18

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    End point title
    Serum Levels of Sprifermin/FGF-18
    End point description
    Serum levels of AS902330/FGF-18 could not be analyzed because the serum concentrations were not quantifiable, as serum sprifermin concentrations were below Lower Limit of Quantification (LLOQ). LLOQ=100 picogram/milliliter.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 0, 2 hours post-dose at Week 1, 2 and 3 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days)
    End point values
    Placebo Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    Units: picogram/milliliter
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [1] - Serum levels of AS902330/FGF-18 could not be analyzed.
    [2] - Serum levels of AS902330/FGF-18 could not be analyzed.
    [3] - Serum levels of AS902330/FGF-18 could not be analyzed.
    [4] - Serum levels of AS902330/FGF-18 could not be analyzed.
    [5] - Serum levels of AS902330/FGF-18 could not be analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 5 years
    Adverse event reporting additional description
    Adverse events presented as per Safety Set.Assignments for subjects in Safety Set were based on actual drug received, such that 1subject assigned to Placebo arm who received30mcg was included in Sprifermin30mcg-2Cycles arm and 1subject assigned to Sprifermin30mcg/placebo-2Cycles arm who received 100mcg was included in Sprifermin100mcg-2Cycles arm.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg- 2 Cycles
    Reporting group description
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 30 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Reporting group title
    Sprifermin (AS902330) 100 mcg- 4 Cycles
    Reporting group description
    Subjects received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months.

    Serious adverse events
    Placebo Sprifermin (AS902330) 30 mcg- 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 107 (36.45%)
    35 / 109 (32.11%)
    34 / 111 (30.63%)
    32 / 111 (28.83%)
    41 / 109 (37.61%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoid tumour
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoid tumour of the gastrointestinal tract
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    2 / 111 (1.80%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Removal of internal fixation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    2 / 111 (1.80%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colpocele
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulvar dysplasia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    2 / 111 (1.80%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    2 / 111 (1.80%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    2 / 111 (1.80%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    2 / 111 (1.80%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arachnoid cyst
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrom
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningeal disorder
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    2 / 111 (1.80%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia obstructive
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loose tooth
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Panniculitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neck obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    9 / 107 (8.41%)
    10 / 109 (9.17%)
    7 / 111 (6.31%)
    7 / 111 (6.31%)
    7 / 109 (6.42%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
    0 / 7
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 109 (1.83%)
    3 / 111 (2.70%)
    0 / 111 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 107 (0.00%)
    4 / 109 (3.67%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Torticollis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
    4 / 111 (3.60%)
    1 / 111 (0.90%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 109 (0.00%)
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Sprifermin (AS902330) 30 mcg- 2 Cycles Sprifermin (AS902330) 30 mcg- 4 Cycles Sprifermin (AS902330) 100 mcg/Placebo (2 cycles) Sprifermin (AS902330) 100 mcg- 4 Cycles
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 107 (98.13%)
    106 / 109 (97.25%)
    109 / 111 (98.20%)
    106 / 111 (95.50%)
    107 / 109 (98.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 107 (15.89%)
    24 / 109 (22.02%)
    14 / 111 (12.61%)
    20 / 111 (18.02%)
    21 / 109 (19.27%)
         occurrences all number
    17
    24
    14
    20
    21
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    6 / 107 (5.61%)
    5 / 109 (4.59%)
    10 / 111 (9.01%)
    4 / 111 (3.60%)
    8 / 109 (7.34%)
         occurrences all number
    6
    5
    10
    4
    8
    Injection site bruising
         subjects affected / exposed
    4 / 107 (3.74%)
    5 / 109 (4.59%)
    6 / 111 (5.41%)
    2 / 111 (1.80%)
    4 / 109 (3.67%)
         occurrences all number
    4
    5
    6
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 107 (8.41%)
    12 / 109 (11.01%)
    12 / 111 (10.81%)
    6 / 111 (5.41%)
    9 / 109 (8.26%)
         occurrences all number
    9
    12
    12
    6
    9
    Oropharyngeal pain
         subjects affected / exposed
    7 / 107 (6.54%)
    1 / 109 (0.92%)
    1 / 111 (0.90%)
    2 / 111 (1.80%)
    3 / 109 (2.75%)
         occurrences all number
    7
    1
    1
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 109 (0.00%)
    7 / 111 (6.31%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    3
    0
    7
    6
    2
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 109 (1.83%)
    0 / 111 (0.00%)
    3 / 111 (2.70%)
    6 / 109 (5.50%)
         occurrences all number
    3
    2
    0
    3
    6
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    18 / 107 (16.82%)
    9 / 109 (8.26%)
    9 / 111 (8.11%)
    9 / 111 (8.11%)
    7 / 109 (6.42%)
         occurrences all number
    18
    9
    9
    9
    7
    Contusion
         subjects affected / exposed
    5 / 107 (4.67%)
    9 / 109 (8.26%)
    9 / 111 (8.11%)
    4 / 111 (3.60%)
    9 / 109 (8.26%)
         occurrences all number
    5
    9
    9
    4
    9
    Ligament sprain
         subjects affected / exposed
    6 / 107 (5.61%)
    5 / 109 (4.59%)
    6 / 111 (5.41%)
    2 / 111 (1.80%)
    8 / 109 (7.34%)
         occurrences all number
    6
    5
    6
    2
    8
    Skin abrasion
         subjects affected / exposed
    1 / 107 (0.93%)
    5 / 109 (4.59%)
    7 / 111 (6.31%)
    6 / 111 (5.41%)
    7 / 109 (6.42%)
         occurrences all number
    1
    5
    7
    6
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 107 (14.02%)
    14 / 109 (12.84%)
    11 / 111 (9.91%)
    13 / 111 (11.71%)
    18 / 109 (16.51%)
         occurrences all number
    15
    14
    11
    13
    18
    Sciatica
         subjects affected / exposed
    11 / 107 (10.28%)
    8 / 109 (7.34%)
    4 / 111 (3.60%)
    7 / 111 (6.31%)
    7 / 109 (6.42%)
         occurrences all number
    11
    8
    4
    7
    7
    Dizziness
         subjects affected / exposed
    7 / 107 (6.54%)
    3 / 109 (2.75%)
    3 / 111 (2.70%)
    5 / 111 (4.50%)
    10 / 109 (9.17%)
         occurrences all number
    7
    3
    3
    5
    10
    Hypoaesthesia
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 109 (3.67%)
    5 / 111 (4.50%)
    3 / 111 (2.70%)
    3 / 109 (2.75%)
         occurrences all number
    7
    4
    5
    3
    3
    Memory impairment
         subjects affected / exposed
    4 / 107 (3.74%)
    0 / 109 (0.00%)
    6 / 111 (5.41%)
    0 / 111 (0.00%)
    2 / 109 (1.83%)
         occurrences all number
    4
    0
    6
    0
    2
    Eye disorders
    Cataract
         subjects affected / exposed
    8 / 107 (7.48%)
    6 / 109 (5.50%)
    10 / 111 (9.01%)
    6 / 111 (5.41%)
    4 / 109 (3.67%)
         occurrences all number
    8
    6
    10
    6
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 107 (1.87%)
    6 / 109 (5.50%)
    3 / 111 (2.70%)
    6 / 111 (5.41%)
    6 / 109 (5.50%)
         occurrences all number
    2
    5
    3
    6
    6
    Diarrhoea
         subjects affected / exposed
    2 / 107 (1.87%)
    4 / 109 (3.67%)
    4 / 111 (3.60%)
    8 / 111 (7.21%)
    5 / 109 (4.59%)
         occurrences all number
    2
    4
    4
    8
    5
    Gastritis
         subjects affected / exposed
    4 / 107 (3.74%)
    4 / 109 (3.67%)
    4 / 111 (3.60%)
    4 / 111 (3.60%)
    6 / 109 (5.50%)
         occurrences all number
    4
    4
    4
    4
    6
    Toothache
         subjects affected / exposed
    5 / 107 (4.67%)
    2 / 109 (1.83%)
    4 / 111 (3.60%)
    7 / 111 (6.31%)
    3 / 109 (2.75%)
         occurrences all number
    5
    2
    4
    7
    3
    Dyspepsia
         subjects affected / exposed
    4 / 107 (3.74%)
    7 / 109 (6.42%)
    2 / 111 (1.80%)
    1 / 111 (0.90%)
    3 / 109 (2.75%)
         occurrences all number
    4
    7
    2
    1
    3
    Abdominal pain
         subjects affected / exposed
    3 / 107 (2.80%)
    3 / 109 (2.75%)
    2 / 111 (1.80%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    3
    3
    2
    6
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
    1 / 111 (0.90%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    2
    1
    1
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    58 / 107 (54.21%)
    59 / 109 (54.13%)
    57 / 111 (51.35%)
    55 / 111 (49.55%)
    54 / 109 (49.54%)
         occurrences all number
    58
    59
    57
    55
    54
    Back pain
         subjects affected / exposed
    24 / 107 (22.43%)
    28 / 109 (25.69%)
    29 / 111 (26.13%)
    33 / 111 (29.73%)
    27 / 109 (24.77%)
         occurrences all number
    24
    28
    29
    33
    27
    Osteoarthritis
         subjects affected / exposed
    21 / 107 (19.63%)
    22 / 109 (20.18%)
    24 / 111 (21.62%)
    17 / 111 (15.32%)
    17 / 109 (15.60%)
         occurrences all number
    21
    22
    24
    17
    17
    Musculoskeletal pain
         subjects affected / exposed
    20 / 107 (18.69%)
    16 / 109 (14.68%)
    18 / 111 (16.22%)
    21 / 111 (18.92%)
    21 / 109 (19.27%)
         occurrences all number
    20
    16
    18
    21
    21
    Pain in extremity
         subjects affected / exposed
    15 / 107 (14.02%)
    12 / 109 (11.01%)
    24 / 111 (21.62%)
    18 / 111 (16.22%)
    20 / 109 (18.35%)
         occurrences all number
    15
    12
    24
    18
    20
    Joint swelling
         subjects affected / exposed
    10 / 107 (9.35%)
    14 / 109 (12.84%)
    11 / 111 (9.91%)
    12 / 111 (10.81%)
    14 / 109 (12.84%)
         occurrences all number
    10
    14
    11
    12
    14
    Neck pain
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 109 (3.67%)
    9 / 111 (8.11%)
    9 / 111 (8.11%)
    7 / 109 (6.42%)
         occurrences all number
    7
    4
    9
    9
    7
    Spinal pain
         subjects affected / exposed
    5 / 107 (4.67%)
    1 / 109 (0.92%)
    5 / 111 (4.50%)
    6 / 111 (5.41%)
    10 / 109 (9.17%)
         occurrences all number
    5
    1
    5
    6
    10
    Muscle spasms
         subjects affected / exposed
    6 / 107 (5.61%)
    4 / 109 (3.67%)
    4 / 111 (3.60%)
    1 / 111 (0.90%)
    10 / 109 (9.17%)
         occurrences all number
    6
    4
    4
    1
    10
    Myalgia
         subjects affected / exposed
    4 / 107 (3.74%)
    4 / 109 (3.67%)
    8 / 111 (7.21%)
    3 / 111 (2.70%)
    6 / 109 (5.50%)
         occurrences all number
    4
    4
    8
    3
    6
    Periarthritis
         subjects affected / exposed
    3 / 107 (2.80%)
    8 / 109 (7.34%)
    5 / 111 (4.50%)
    5 / 111 (4.50%)
    4 / 109 (3.67%)
         occurrences all number
    3
    8
    5
    5
    4
    Plantar fasciitis
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 109 (5.50%)
    7 / 111 (6.31%)
    4 / 111 (3.60%)
    4 / 109 (3.67%)
         occurrences all number
    3
    6
    7
    4
    4
    Tendonitis
         subjects affected / exposed
    2 / 107 (1.87%)
    8 / 109 (7.34%)
    2 / 111 (1.80%)
    4 / 111 (3.60%)
    4 / 109 (3.67%)
         occurrences all number
    2
    8
    2
    4
    4
    Arthritis
         subjects affected / exposed
    2 / 107 (1.87%)
    4 / 109 (3.67%)
    2 / 111 (1.80%)
    6 / 111 (5.41%)
    3 / 109 (2.75%)
         occurrences all number
    2
    4
    2
    6
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 107 (19.63%)
    25 / 109 (22.94%)
    28 / 111 (25.23%)
    28 / 111 (25.23%)
    30 / 109 (27.52%)
         occurrences all number
    21
    25
    28
    28
    30
    Nasopharyngitis
         subjects affected / exposed
    27 / 107 (25.23%)
    25 / 109 (22.94%)
    20 / 111 (18.02%)
    19 / 111 (17.12%)
    22 / 109 (20.18%)
         occurrences all number
    27
    25
    20
    19
    22
    Urinary tract infection
         subjects affected / exposed
    10 / 107 (9.35%)
    13 / 109 (11.93%)
    10 / 111 (9.01%)
    13 / 111 (11.71%)
    17 / 109 (15.60%)
         occurrences all number
    10
    13
    10
    13
    17
    Influenza
         subjects affected / exposed
    13 / 107 (12.15%)
    10 / 109 (9.17%)
    11 / 111 (9.91%)
    12 / 111 (10.81%)
    12 / 109 (11.01%)
         occurrences all number
    13
    10
    11
    12
    12
    Cystitis
         subjects affected / exposed
    7 / 107 (6.54%)
    15 / 109 (13.76%)
    8 / 111 (7.21%)
    9 / 111 (8.11%)
    10 / 109 (9.17%)
         occurrences all number
    7
    15
    8
    9
    10
    Bronchitis
         subjects affected / exposed
    10 / 107 (9.35%)
    11 / 109 (10.09%)
    6 / 111 (5.41%)
    6 / 111 (5.41%)
    9 / 109 (8.26%)
         occurrences all number
    10
    11
    6
    6
    9
    Pneumonia
         subjects affected / exposed
    6 / 107 (5.61%)
    9 / 109 (8.26%)
    7 / 111 (6.31%)
    6 / 111 (5.41%)
    3 / 109 (2.75%)
         occurrences all number
    6
    9
    7
    6
    3
    Viral infection
         subjects affected / exposed
    5 / 107 (4.67%)
    6 / 109 (5.50%)
    4 / 111 (3.60%)
    4 / 111 (3.60%)
    4 / 109 (3.67%)
         occurrences all number
    5
    6
    4
    4
    4
    Gastroenteritis
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 109 (2.75%)
    7 / 111 (6.31%)
    7 / 111 (6.31%)
    2 / 109 (1.83%)
         occurrences all number
    0
    3
    7
    7
    2
    Herpes zoster
         subjects affected / exposed
    3 / 107 (2.80%)
    5 / 109 (4.59%)
    2 / 111 (1.80%)
    3 / 111 (2.70%)
    6 / 109 (5.50%)
         occurrences all number
    3
    5
    2
    3
    6
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    4 / 107 (3.74%)
    5 / 109 (4.59%)
    3 / 111 (2.70%)
    10 / 111 (9.01%)
    7 / 109 (6.42%)
         occurrences all number
    4
    5
    3
    10
    7
    Hyperlipidaemia
         subjects affected / exposed
    3 / 107 (2.80%)
    7 / 109 (6.42%)
    4 / 111 (3.60%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    3
    7
    4
    6
    2
    Diabetes mellitus
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 109 (5.50%)
    3 / 111 (2.70%)
    6 / 111 (5.41%)
    3 / 109 (2.75%)
         occurrences all number
    3
    6
    3
    6
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2013
    - Inclusion criterion for joint space width (JSW) of > 3.0 mm was changed to JSW > 2.5 mm based on data from recently published clinical trials - Clarified that according to the criteria of the American College of Rheumatology (ACR), subjects should report a history of pain on most days, i.e. more than half of the days of the previous month - Modified the drug washout requirement for subjects who are using analgesic/anti-inflammatory drugs to manage OA pain - Restriction on the concomitant use of short-term corticosteroids for a condition other than OA was changed to allow for low-dose or short term use of corticosteroids for concomitant medical conditions (e.g., allergic or respiratory conditions) - The number of study sites was reduced based on the decision to use a network of sites with extensive experience in conducting these types of OA trials with a well-built history of subject recruitment.

    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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