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    Clinical Trial Results:
    A multiple-dose, subject- and investigator-blinded, placebo-controlled, parallel design study to assess the efficacy, safety, and tolerability of ACZ885 (canakinumab) in pediatric and young adult patients with sickle cell anemia.

    Summary
    EudraCT number
    		 2016-002101-19
    Trial protocol
    		 GB   DE  
    Global end of trial date
    27 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2020
    First version publication date
    12 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885X2206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02961218
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to determine the effect of ACZ885 versus placebo on daily pain experienced by SCA subjects.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    		 Subjects were maintained on their pre-existing stable medical regimen for treatment of preexisting medical conditions, including SCA. Common potential concomitant medications in this study population were anticipated to include analgesics and stable hydroxyurea therapy, defined as a hydroxyurea dosing regimen that remained fixed except for any adjustments according to hematologic parameters or other standard of care clinical monitoring. All prescription medications, over-the-counter drugs and significant non-drug therapies (including physical therapy and blood transfusions) administered or taken within the timeframe defined in the entry criteria prior to the start of the study and during the study was recorded on the concomitant medications/significant non-drug therapies section of the CRF.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    49
    EEA total number of subjects
    14
    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)
    4
    Adolescents (12-17 years)
    28
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 49 participants were randomized into the study from 15 centers in seven countries: Greater Britain (5), Israel (1), Germany (1), Turkey (3), South Africa (1), USA (3) and Canada (1).

    Pre-assignment
    Screening details
    		 Subjects who met the eligibility criteria at screening underwent evaluation of baseline clinical and biomarker assessments prior to first dose administration.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ACZ885
    Arm description
    		 Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Arm title
    		 Placebo
    Arm description
    		 Monthly doses of placebo to match the administered dose of ACZ885 s.c.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Monthly doses of placebo to match the administered dose of canakinumab s.c.

    Number of subjects in period 1
    		ACZ885 Placebo
    Started
    25
    24
    Safety analysis set
    25
    24
    Primary PD analysis set
    25
    24
    Completed
    22
    19
    Not completed
    3
    5
         Physician decision
    -
    2
         Subject/Guardian Decision
    3
    1
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ACZ885
    Reporting group description
    		 Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Reporting group title
    Placebo
    Reporting group description
    		 Monthly doses of placebo to match the administered dose of ACZ885 s.c.

    Reporting group values
    		 ACZ885 Placebo Total
    Number of subjects
    		 25 24 49
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 2 2 4
        Adolescents (12-17 years)
    		 14 14 28
        Adults (18-64 years)
    		 9 8 17
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 15.8 ± 2.69 15.6 ± 3.28 -
    Sex: Female, Male
    Units: Participants
        Female
    		 10 11 21
        Male
    		 15 13 28
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 12 13 25
        White
    		 12 10 22
        Other
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    ACZ885
    Reporting group description
    		 Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Reporting group title
    Placebo
    Reporting group description
    		 Monthly doses of placebo to match the administered dose of ACZ885 s.c.

    Primary: Change from baseline of 4- week average daily pain measured by Visual analog score (VAS) over the period of Week 8 to 12

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    End point title
    		 Change from baseline of 4- week average daily pain measured by Visual analog score (VAS) over the period of Week 8 to 12
    End point description
    Visual analog scale (VAS) was used to record severity. Pediatric and young adult participants rated their daily sickle cell associated pain intensity once each day in the evening using an 11-point numerical rating scale from 0 to 10 with higher ratings associated with more intense pain (0 = no pain, 10 = worst pain). For each subject, there was a maximum 28-day screening period that included recording of daily pain intensity by e-diary for at least 1 week. The average daily pain results in the screening period were used to derive the baseline value. The average over week 8 to 12 was calculated and the change from baseline in the average daily pain VAS was analyzed using a Bayesian model for repeated measures.
    End point type
    Primary
    End point timeframe
    Baseline (upto 28 days prior to start of treatment), Week 8 to 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    25
    24
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.45 ± 0.384
    -0.37 ± 0.402
    Statistical analysis title
    		 Change in average daily-pain
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55 [1]
    Method
    		 Bayesian model for repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.85
    Variability estimate
    Standard deviation
    Dispersion value
    0.57
    Notes
    [1] - probability reduction of average pain score in ACZ885 > Placebo

    Secondary: Change from baseline of average daily pain VAS over 4 weeks intervals up to Week 24

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    End point title
    		 Change from baseline of average daily pain VAS over 4 weeks intervals up to Week 24
    End point description
    Visual analog scale (VAS) was used to record severity. Pediatric and young adult participants rated their daily sickle cell associated pain intensity once each day in the evening using an 11-point numerical rating scale from 0 to 10 with higher ratings associated with more intense pain (0 = no pain, 10 = worst pain). The average of 4 weeks interval up to week 24 was calculated.
    End point type
    Secondary
    End point timeframe
    Baseline (upto 28 days prior to start of treatment), Week 0 to 4, Week 4 to 8, Week 8 to 12, Week 12 to 16, Week 16 to 20 and Week 20 to 24
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    25
    24
    Units: Score on a scale
    arithmetic mean (standard deviation)
        0-4 Weeks
    -0.337 ± 1.629
    0.007 ± 1.428
        4-8 Weeks
    -0.173 ± 1.515
    0.158 ± 1.847
        8-12 Weeks
    -0.444 ± 1.437
    -0.376 ± 2.104
        12-16 Weeks
    -0.505 ± 1.744
    0.057 ± 2.371
        16-20 Weeks
    -0.388 ± 1.772
    0.151 ± 1.811
        20-24 Weeks
    -0.752 ± 1.678
    0.036 ± 2.131
    No statistical analyses for this end point

    Secondary: Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) from Baseline to Week 12

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    End point title
    		 Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) from Baseline to Week 12
    End point description
    hs-CRP is a biomarker that represents the inflammation process.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    20
    19
    Units: mg/L
        least squares mean (confidence interval 90%)
    0.338 (0.237 to 0.483)
    0.830 (0.576 to 1.194)
    Statistical analysis title
    		 Change in concentration of hsCRP
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed-effect Model for Repeated Measures
    Parameter type
    		 Ratio
    Point estimate
    0.408
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.253
         upper limit
    		 0.658

    Secondary: Change in the Concentration of White Blood Cell (WBC) count from baseline to Week 12

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    End point title
    		 Change in the Concentration of White Blood Cell (WBC) count from baseline to Week 12
    End point description
    WBC count was used as a laboratory marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    19
    17
    Units: 10^9/liter
        least squares mean (confidence interval 90%)
    0.813 (0.737 to 0.898)
    1.081 (0.973 to 1.201)
    Statistical analysis title
    		 Change in concentration of WBC count
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed-effect Model for Repeated Measures
    Parameter type
    		 Ratio
    Point estimate
    0.752
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.657
         upper limit
    		 0.862

    Secondary: Change in the Concentration of absolute count of neutrophils from baseline to Week 12

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    End point title
    		 Change in the Concentration of absolute count of neutrophils from baseline to Week 12
    End point description
    Absolute count of neutrophils was measured as a laboratory marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    19
    17
    Units: 10^9/liter
        least squares mean (confidence interval 90%)
    0.717 (0.611 to 0.842)
    1.052 (0.888 to 1.246)
    Statistical analysis title
    		 Change in absolute count of neutrophils
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed-effect Model for Repeated Measures
    Parameter type
    		 Ratio
    Point estimate
    0.682
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.547
         upper limit
    		 0.849

    Secondary: Change in the Concentration of absolute count of blood monocytes from baseline to Week 12

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    End point title
    		 Change in the Concentration of absolute count of blood monocytes from baseline to Week 12
    End point description
    Absolute count of blood monocytes was measured as a laboratory marker to determine the effect of the drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    19
    17
    Units: 10^9/liter
        least squares mean (confidence interval 90%)
    0.712 (0.590 to 0.859)
    0.992 (0.813 to 1.209)
    Statistical analysis title
    		 Change in absolute count of blood monocytes
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 Mixed-effect Model for Repeated Measures
    Parameter type
    		 Ratio
    Point estimate
    0.718
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.556
         upper limit
    		 0.925

    Secondary: Change in the Concentration of Hemoglobin from baseline to Week 12

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    End point title
    		 Change in the Concentration of Hemoglobin from baseline to Week 12
    End point description
    Hemoglobin was used as a hemolysis marker to determine the effect of the drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    19
    19
    Units: g/L
        arithmetic mean (standard deviation)
    -0.97 ± 4.727
    1.11 ± 7.975
    No statistical analyses for this end point

    Secondary: Change in the reticulocyte count from baseline to Week 12

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    End point title
    		 Change in the reticulocyte count from baseline to Week 12
    End point description
    Reticulocyte count was used as a hemolysis marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    18
    19
    Units: 10^9/liter
        arithmetic mean (standard deviation)
    -6.578 ± 64.1131
    25.358 ± 47.6483
    No statistical analyses for this end point

    Secondary: Change in the Concentration of bilirubin from baseline to Week 12

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    End point title
    		 Change in the Concentration of bilirubin from baseline to Week 12
    End point description
    Bilirubin was used as a hemolysis marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    20
    19
    Units: umol/L
        arithmetic mean (standard deviation)
    5.05 ± 19.796
    -1.95 ± 11.591
    No statistical analyses for this end point

    Secondary: Change in the Concentration of Lactate Dehydrogenase (LDH) from baseline to Week 12

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    End point title
    		 Change in the Concentration of Lactate Dehydrogenase (LDH) from baseline to Week 12
    End point description
    LDH was used as a hemolysis marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    18
    19
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    19.06 ± 70.862
    -33.74 ± 209.259
    No statistical analyses for this end point

    Secondary: Change in the Concentration of haptoglobin from baseline to Week 12

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    End point title
    		 Change in the Concentration of haptoglobin from baseline to Week 12
    End point description
    Haptoglobin was used as a hemolysis marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    13
    19
    Units: g/L
        arithmetic mean (standard deviation)
    -0.0112 ± 0.04022
    -0.0213 ± 0.07923
    No statistical analyses for this end point

    Secondary: Change in the Concentration of oxygen percent saturation (SAO2) from baseline to Week 12

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    End point title
    		 Change in the Concentration of oxygen percent saturation (SAO2) from baseline to Week 12
    End point description
    SAO2 was used as a hemolysis marker to determine the effect of the drug
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    20
    19
    Units: Oxygen Saturation Percent
        arithmetic mean (standard deviation)
    -0.5 ± 2.16
    -0.3 ± 1.82
    No statistical analyses for this end point

    Secondary: Number of days absent from school or work due to pain as recorded by e-diary

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    End point title
    		 Number of days absent from school or work due to pain as recorded by e-diary
    End point description
    The number of SCA-related days absent from school or work were derived from eDiary records.
    End point type
    Secondary
    End point timeframe
    up to Week 24
    End point values
    		 ACZ885 Placebo
    Number of subjects analysed
    22
    19
    Units: Days
        arithmetic mean (confidence interval 90%)
    2.20 (1.69 to 2.70)
    1.86 (1.31 to 2.41)
    Statistical analysis title
    		 SCA-related days absent from school/work
    Comparison groups
    ACZ885 v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.455
    Method
    		 Generalized Linear Model (GLM)
    Parameter type
    		 Ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45

    Secondary: Mean serum concentration after repeated dosing of ACZ885

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    End point title
    		 Mean serum concentration after repeated dosing of ACZ885 [2]
    End point description
    PK samples were collected at Baseline, Week 4, 12, 20 and 24. Mean and standard deviation of the ACZ885 concentration was reported. Only those participants available at the specified time points were analyzed
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 12, 20 and 24
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo patients were excluded from the PK analyses.
    End point values
    		 ACZ885
    Number of subjects analysed
    25
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline
    0 ± 0
        Week 4
    13100 ± 5490
        Week 12
    18700 ± 5860
        Week 20
    19700 ± 5810
        Week 24
    20600 ± 5930
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment (Week 48) plus 8 weeks post treatment, up to maximum duration of 56 weeks.
    Adverse event reporting additional description
    Any sign or symptom collected in the double-blinded period i.e 24 weeks followed by an additional 24-week open label phase (optional). Adverse events were reported separately for the double-blind and the open-label phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    ACZ885
    Reporting group description
    		 Double-blind period (Week 0 to 24): Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Reporting group title
    Placebo
    Reporting group description
    		 Double-blind period (Week 0 to 24): Monthly doses of placebo to match the administered dose of ACZ885 s.c.

    Reporting group title
    ACZ885 / ACZ885
    Reporting group description
    		 Open label Phase (after Week 24 to Week 56) for the participants originally randomized to ACZ885: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Reporting group title
    Placebo / ACZ885
    Reporting group description
    		 Open label Phase (after Week 24 to Week 56) for the participants originally randomized to placebo: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects

    Serious adverse events
    		 ACZ885 Placebo ACZ885 / ACZ885 Placebo / ACZ885
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 25 (44.00%)
    15 / 24 (62.50%)
    11 / 22 (50.00%)
    11 / 20 (55.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Aplasia pure red cell
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    10 / 25 (40.00%)
    11 / 24 (45.83%)
    9 / 22 (40.91%)
    10 / 20 (50.00%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 28
    0 / 26
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Alloimmunisation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Priapism
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ACZ885 Placebo ACZ885 / ACZ885 Placebo / ACZ885
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 25 (76.00%)
    20 / 24 (83.33%)
    17 / 22 (77.27%)
    18 / 20 (90.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign lymph node neoplasm
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Meningioma
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    3
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Injection site pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Medical device site irritation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    3 / 22 (13.64%)
    2 / 20 (10.00%)
         occurrences all number
    2
    1
    3
    2
    Pain
         subjects affected / exposed
    6 / 25 (24.00%)
    5 / 24 (20.83%)
    3 / 22 (13.64%)
    7 / 20 (35.00%)
         occurrences all number
    11
    11
    7
    18
    Pyrexia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Immune system disorders
    Allergy to metals
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    1
    Polymenorrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Priapism
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    6
    0
    9
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Pharyngeal swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Illness anxiety disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pica
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Oxygen saturation abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Spleen palpable
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ultrasound Doppler abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Vitamin B12 decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wrist fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Benign enlargement of the subarachnoid spaces
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    1
    2
    Headache
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 24 (12.50%)
    2 / 22 (9.09%)
    4 / 20 (20.00%)
         occurrences all number
    8
    7
    3
    11
    Lethargy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Spinal cord oedema
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    1
    Thrombocytosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    1
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    1
    3
    Diarrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lip swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    0
    4
    Swollen tongue
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    3
    Rash
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Xeroderma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nephropathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal colic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    4
    0
    2
    1
    Back pain
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 24 (8.33%)
    2 / 22 (9.09%)
    5 / 20 (25.00%)
         occurrences all number
    3
    4
    2
    14
    Bone infarction
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Degenerative bone disease
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle swelling
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Osteonecrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Osteoporosis
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 24 (12.50%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    7
    16
    0
    10
    Pain in jaw
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Spinal deformity
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    1
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    2
    Tonsillitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 24 (20.83%)
    2 / 22 (9.09%)
    6 / 20 (30.00%)
         occurrences all number
    1
    7
    2
    9
    Urinary tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 24 (4.17%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    3
    2
    Viral infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin B complex deficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Vitamin D deficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2016
    The protocol was amended to implement the changes requested by the Medicines and Healthcare Products Regulatory Agency (UK): - The protocol was updated to reflect the contraceptive advice in the Summary of Product Characteristics i.e. Women should use effective contraceptives during treatment and for up to 3 months after the last dose. - Pregnancy testing was performed monthly in sexually active females. Additional changes were implemented to ensure consistency thought the protocol and to add clarifications to some sections.
    14 Jun 2017
    The protocol was amended to implement the changes requested by the Food and Drug Administration (FDA) to clarify the stopping rules by applying a threshold of 20% higher SAE rate in the ACZ885 arm compared to placebo arm to identify an overt change in the SAE incidence rate.
    09 Aug 2017
    The protocol was amended to improve clarity and update elements of secondary and exploratory outcomes, study design, inclusion/exclusion criteria, stopping rules and data analysis based on study investigators’ input and initial trial experience. In addition, total volume requirements for blood sampling were reduced.
    03 Nov 2017
    The protocol was amended to implement changes requested by the German Health Authority (Paul Ehrlich Institut) concerning exclusion criteria, study design wording and elements of the data analysis plan.
    22 Mar 2018
    The protocol was amended to implement changes to inclusion and exclusion criteria such as expanding age range to 8-20 years to improve the feasibility of study recruitment and implementation – which was based on feedback from Investigators

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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