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    Clinical Trial Results:
    A pilot open-label study to assess the efficacy and safety of tocilizumab (TCZ) in patients with active Schnitzler’s syndrome (SchS)

    Summary
    EudraCT number
    		 2016-003828-23
    Trial protocol
    		 DE  
    Global end of trial date
    10 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions
    Summary report(s)
    		 final report_ML39310

    Trial information

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    Trial identification
    Sponsor protocol code
    ML39310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03046381
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Karoline Krause, Charité - Universitätsmedizin Berlin; Dpt. of Dermatology and Allergy, 0049 30450518336, karoline.krause@charite.de
    Scientific contact
    Karoline Krause, Charité - Universitätsmedizin Berlin; Dpt. of Dermatology and Allergy, 0049 30450518336, karoline.krause@charite.de
    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
    10 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of TCZ on the clinical signs and symptoms of SchS. This study is a pilot study intended to provide efficacy, safety and tolerability data in a small patient population of SchS. With the small sample size and the unknown variability of the disease activity assessments in this population, statistical power considerations are unwarranted in principle. Due to the limited patient numbers with SchS, the sample size is not based on statistical methodology but reflects the number of patients that are currently treated at the Autoinflammation Reference Center Charité and thought to willing and suitable to participate in the study
    Protection of trial subjects
    Safety parameters were documented at each study visit and reported accordingly. Safety parameters included adverse events, laboratory values, clinical monitoring, and prescribed clinic visits.
    Background therapy
    		 Tocilizumab ((RoActemra®, L04AC07,Roche/Chugai, CH-4070 Basel, Switzerland) is a recombinant humanized, anti-human monoclonal antibody of the IgG1 sub-class directed against the soluble (sIL-6R) and membrane-bound interleukin-6 receptor (mIL-6R). Interleukin-6 (IL-6) is a key mediator of local and systemic inflammatory reactions. The final tocilizumab drug has intravenous (IV) and subcutaneous (SC) formulations. Tocilizumab (IV and SC formulations) is indicated for adults for treatment of moderate to severe active rheumatoid arthritis (RA) in E.U. and U.S.. Moreover, tocilizumab (IV formulation) is approved for children 2 years of age and older for treatment of polyarticularcourse juvenile idiopathic arthritis (pJIA) and systemic juvenile idiopathic arthritis (sJIA) in E.U. and U.S.. In India and Japan, tocilizumab is approved for treatment of Castleman’s disease. Clinical studies were conducted for Crohn’s disease, multiple myeloma, systemic lupus erythematosus, ankylosing spondylitis and B-cell chronic lymphocytic leukemia, but tocilizumab is no longer being developed for these indications. Moreover, tocilizumab has been shown to be effective in severe uveitis associated with Behçet’s disease. Effective treatment of single patients with autoinflammatory diseases tumor necrosis factor receptor-associated periodic syndrome (TRAPS) as well as Schnitzler’s syndrome has been reported.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2017
    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
    Germany: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in Germany, between July 2017 (first patient first visit) and March 2019 (last patient last visit).

    Pre-assignment
    Screening details
    		 Screening details: N=9 patients entered the initial screening phase of the study. N=8 patients were eligible for the study and entered the treatment phase. N=4 patients discontinued the study. N=4 patients completed the study.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tocilizumab 162mg
    Arm description
    		 This study is a pilot study intended to provide efficacy, safety and tolerability data in a small patient population of SchS. With the small sample size and the unknown variability of the disease activity assessments in this population, statistical power considerations are unwarranted in principle. Due to the limited patient numbers with SchS, the sample size is not based on statistical methodology but reflects the number of patients that are currently treated at the Autoinflammation Reference Center Charité and thought to willing and suitable to participate in the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab 162mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    162 mg subcutaneous injections every week within 52 weeks.

    Number of subjects in period 1
    		Tocilizumab 162mg
    Started
    8
    Completed
    4
    Not completed
    4
         Adverse event, non-fatal
    2
         Lack of efficacy
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 -

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 8 8
    Age categorical
    Units: Subjects
        Adults over 18 years
    		 8 8
    Gender categorical
    Units: Subjects
        Male/Female
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab 162mg
    Reporting group description
    		 This study is a pilot study intended to provide efficacy, safety and tolerability data in a small patient population of SchS. With the small sample size and the unknown variability of the disease activity assessments in this population, statistical power considerations are unwarranted in principle. Due to the limited patient numbers with SchS, the sample size is not based on statistical methodology but reflects the number of patients that are currently treated at the Autoinflammation Reference Center Charité and thought to willing and suitable to participate in the study.

    Subject analysis set title
    Baseline (Week 0)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    For comparisons between baseline and tocilizumab treatment, primarily descriptive statistics will be used

    Primary: PGA change in the open label phase

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    End point title
    		 PGA change in the open label phase
    End point description
    End point type
    Primary
    End point timeframe
    Week 20
    End point values
    		 Tocilizumab 162mg Baseline (Week 0)
    Number of subjects analysed
    7
    8
    Units: PGA Score
    arithmetic mean (standard deviation)
        Total (0-20)
    3.3 ( 3.6 )
    12.1 ( 2.5 )
        Urticarial rash (0-4)
    1.0 ( 1.5 )
    1.8 ( 1.5 )
        Fatigue (0-4)
    0.6 ( 0.5 )
    2.6 ( 0.7 )
        Fever (0-4)
    0 ( 0 )
    1.4 ( 1.3 )
        Myalgia (0-4)
    0.9 ( 1.1 )
    2.9 ( 0.8 )
        Arthralgia /bone pain (0-4)
    0.9 ( 1.2 )
    3.5 ( 0.5 )
    Statistical analysis title
    		 Descriptive statistics for comparison
    Statistical analysis description
    For comparisons between baseline and tocilizumab treatment, primarily descriptive statistics will be used. For continuous variables, the number of patients reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum, including confidence intervals where applicable, will be assessed. f a sufficient number of subjects is recruited, appropriate statistical tests will be advanced; otherwise, only descriptive statistics will be provided.
    Comparison groups
    Tocilizumab 162mg v Baseline (Week 0)
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - For comparisons between baseline and open-label treatment period with continuous variables and expected normal distribution, a paired t-test will be used. If parametric assumptions are unwarranted, non-parametric analogies such as the Wilcoxon signed rank test will be advanced.

    Secondary: change of the inflammation marker levels

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    End point title
    		 change of the inflammation marker levels
    End point description
    see manuscript: Graphs for CRP, ESR, SAA and S100A8/9 CRP, C reactive Protein; ESR, Erythrocyte sedimentation rates;SAA, Serum Amyloid A;
    End point type
    Secondary
    End point timeframe
    Week 20
    End point values
    		 Tocilizumab 162mg Baseline (Week 0)
    Number of subjects analysed
    7
    8
    Units: mg/l, mm/h and µg/l
    arithmetic mean (standard deviation)
        CRP
    0.6 ( 1.0 )
    31.67 ( 54.1 )
        SAA
    4.1 ( 3.5 )
    176 ( 260.2 )
        ESR
    12.6 ( 13.1 )
    37.6 ( 29.3 )
        S100A8/9
    2.4 ( 1.1 )
    6.6 ( 6.6 )
    No statistical analyses for this end point

    Secondary: Change of the SchAS score

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    End point title
    		 Change of the SchAS score
    End point description
    SchAS (Schnitzler’s syndrome activity score, 0-10); Tocilizumab treatment resulted in reduction of mean total SchAS scores
    End point type
    Secondary
    End point timeframe
    Week 20 (140 Days)
    End point values
    		 Tocilizumab 162mg Baseline (Week 0)
    Number of subjects analysed
    7
    8
    Units: Score
    arithmetic mean (full range (min-max))
        SchAS
    1.5 (0.25 to 2.8)
    2.3 (0.7 to 4.0)
    Attachments
    		 SchAS score
    No statistical analyses for this end point

    Other pre-specified: PGA change in the optional study extension

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    End point title
    		 PGA change in the optional study extension
    End point description
    Change in the investigator’s assessment of total disease activity (Physician global assessment [PGA], a composite score which includes the 5 key clinical symptoms of SchS) between baseline and TCZ treatment
    End point type
    Other pre-specified
    End point timeframe
    52 weeks
    End point values
    		 Tocilizumab 162mg
    Number of subjects analysed
    4
    Units: PGA Score
    arithmetic mean (standard deviation)
        Total (0-20)
    7 ( 4.5 )
        Urticarial rash (0-4)
    2 ( 1.4 )
        Fatigue (0-4)
    1.8 ( 1 )
        Fever (0-4)
    0 ( 0 )
        Myalgia (0-4)
    1.8 ( 1.3 )
        Arthralgia /bone pain (0-4)
    1.5 ( 1.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    During the whole trial.
    Adverse event reporting additional description
    Safety analysis will be performed on the safety population. Summary statistics for all safety variables will include the total number of subjects and the number experiencing the adverse event by body system using MedDRA terminology.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: for Safety Results see attachment: final report_ML39310

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33545397
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