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    Clinical Trial Results:
    A multi-center, double-blind placebo-controlled parallel group phase II study of the efficacy and safety of rilonacept in subjects with cold contact urticaria (CCU)

    Summary
    EudraCT number
    		 2012-005726-30
    Trial protocol
    		 DE  
    Global end of trial date
    14 Mar 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Jul 2022
    First version publication date
    02 Jun 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    correction secondaryl endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    CURES-IL1T-OT-1236
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charitè- Universitätsmedizin Berlin
    Sponsor organisation address
    Chariteplatz 1, Berlin, Germany, 10117
    Public contact
    Allergie-Centrum-Charité, Charité - Universitätsmedizin , +49 30 450 518342, Karoline.Krause@charite.de
    Scientific contact
    Allergie-Centrum-Charité, Charité - Universitätsmedizin , +49 30 450 518342, 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
    09 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of rilonacept on the clinical signs and symptoms of cold contact urticaria
    Protection of trial subjects
    Safety of patients treated with rilonacept 160mg and 320mg: This includes physical examination, routine safety laboratory assessments, vital signs and adverse event reporting. Furthermore, the patients were monitored for spontaneous complaints after treatments. Safety analysis will include examination of treatment-emergent adverse events (TEAE) and changes in vital signs and laboratory tests.
    Background therapy
    		 Rilonacept is a dimeric glycoprotein with a total molecular weight of ~251 kDa, of which 80% is protein (201 kDa), and 20% is carbohydrate (50 kDa). The dimer is covalently linked by disulfide bonds in the Fc region. Rilonacept is expressed recombinantly in Chinese hamster ovary (CHO) cells and is purified with a series of chromatographic and filtration techniques. Rilonacept is similar to etanercept (Enbrel), the TNF antagonist approved for rheumatoid arthritis (RA), in that it is a fusion protein consisting of human cytokine receptor extracellular domains and the Fc portion of human IgG1. Human experience with rilonacept includes 21 clinical studies. In total 2026 patients and 91 healthy volunteers have been exposed to rilonacept. Overall, rilonacept was administered to 383 patients with rheumatoid arthritis, 1511 with gout arthritis, 38 with osteoarthritis, 113 with cryopyrin associated periodic syndromes (CAPS), like familial cold autoinflammatory syndrome (FCAS) and Muckle-wells syndrome(MWS), 15 with systemic juvenile arthritis, 6 with end stage renal disease, 26 with coronary artery disease and 6 with rheumatic polymyalgia. Another pilot, open-label study (investigator-initiated trial) was performed in 2 patients with MWS and 8 patients with Schnitzler syndrome at the Dept. of Dermatology and Allergy, Charité-Universitätsmedizin Berlin to assess the the safety and tolerability and efficacy of rilonacept in these patients.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jun 2013
    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
    Germany: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 2 study centers in Germany, between 02/19/2015 (first patient first visit) and 03/14/2018 (last patient last visit).

    Pre-assignment
    Screening details
    		 All patients included in this study will be subjected at the screening visit, V1 (d-14) to physical examination, vital signs assessment, electrocardiogram, QuantiFERON TB test, serum pregnancy test and basic laboratory control (hematology panel, chemistry panel, CRP and urinalysis).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rilonacept 160mg
    Arm description
    		 Rilonacept s.c every 7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept
    Investigational medicinal product code
    Other name
    Arcalyst
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    160 mg per week and from day 0 to day 42

    Arm title
    		 Placebo
    Arm description
    		 Placebo s.c every 7 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    same as in the Rilonacept arm

    Number of subjects in period 1
    		Rilonacept 160mg Placebo
    Started
    11
    9
    Completed
    10
    9
    Not completed
    1
    0
         unknown
    1
    -
    Period 2
    Period 2 title
    Open label phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    no blinding during open label study

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rilonacept 160mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept
    Investigational medicinal product code
    Other name
    Arcalyst
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    160 mg per week and from day 0 to day 42

    Arm title
    		 Rilonacept 320mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept 320mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Rilonacept 320mg injection (s.c.)

    Number of subjects in period 2
    		Rilonacept 160mg Rilonacept 320mg
    Started
    9
    3
    Completed
    8
    3
    Not completed
    1
    0
         unknown
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    Age categorical
    Adult ( 18 years of age)
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 45.55 (33 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 13 13
    CTT
    Critical temperature threshold
    Units: celsius temperature
        arithmetic mean (standard deviation)
    		 19.5 ( 5.2 ) -
    Duration of cold urticaria
    Units: Months
        arithmetic mean (standard deviation)
    		 156 ( 167.9 ) -
    BMI
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 27.54 ( 4.9 ) -
    Subject analysis sets

    Subject analysis set title
    Rilonacept 320mg (open label)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    3 Patients were accepted from the double blind study phase

    Subject analysis sets values
    		 Rilonacept 320mg (open label)
    Number of subjects
    2
    Age categorical
    Adult ( 18 years of age)
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    59 (49 to 72)
    Gender categorical
    Units: Subjects
        Female
    1
        Male
    2
    CTT
    Critical temperature threshold
    Units: celsius temperature
        arithmetic mean (standard deviation)
    17 ( 12.73 )
    Duration of cold urticaria
    Units: Months
        arithmetic mean (standard deviation)
    200 ( 100.6 )
    BMI
    Units: kg/m²
        arithmetic mean (standard deviation)
    25 ( 4.5 )

    End points

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    End points reporting groups
    Reporting group title
    Rilonacept 160mg
    Reporting group description
    		 Rilonacept s.c every 7 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo s.c every 7 days
    Reporting group title
    Rilonacept 160mg
    Reporting group description
    		 -

    Reporting group title
    Rilonacept 320mg
    Reporting group description
    		 -

    Subject analysis set title
    Rilonacept 320mg (open label)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    3 Patients were accepted from the double blind study phase

    Primary: change in critical temperature thresholds (CTT)

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    End point title
    		 change in critical temperature thresholds (CTT)
    End point description
    End point type
    Primary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Placebo
    Number of subjects analysed
    10
    9
    Units: °C
        arithmetic mean (standard deviation)
    0.89 ( 4.6 )
    -0.44 ( 3.43 )
    Statistical analysis title
    		 Test of critical temperature thresholds
    Comparison groups
    Rilonacept 160mg v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: change in critical temperature thresholds (CTT) (open label)

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    End point title
    		 change in critical temperature thresholds (CTT) (open label)
    End point description
    End point type
    Primary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Rilonacept 320mg
    Number of subjects analysed
    9
    2
    Units: °C
        arithmetic mean (standard deviation)
    -1 ( 4.03 )
    2 ( 5.7 )
    Statistical analysis title
    		 CTT (open label)
    Comparison groups
    Rilonacept 320mg v Rilonacept 160mg
    Number of subjects included in analysis
    11
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Dermatology Life Quality Index

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    End point title
    		 Dermatology Life Quality Index
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Placebo
    Number of subjects analysed
    10
    9
    Units: total scores
        arithmetic mean (standard deviation)
    -3.8 ( 2.7 )
    0.0 ( 3.8 )
    No statistical analyses for this end point

    Secondary: disease intensity

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    End point title
    		 disease intensity
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Placebo
    Number of subjects analysed
    10
    9
    Units: scores
        arithmetic mean (standard deviation)
    1.1 ( 4.1 )
    1.78 ( 6.2 )
    Statistical analysis title
    		 disease intensity
    Comparison groups
    Rilonacept 160mg v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Dermatology Life Quality Index (open label)

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    End point title
    		 Dermatology Life Quality Index (open label)
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Rilonacept 320mg
    Number of subjects analysed
    9
    2
    Units: total scores
        arithmetic mean (standard deviation)
    -0.36 ( 4.8 )
    -4.5 ( 2.12 )
    Statistical analysis title
    		 DLQI (open label)
    Comparison groups
    Rilonacept 320mg v Rilonacept 160mg
    Number of subjects included in analysis
    11
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: disease intensity (open label)

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    End point title
    		 disease intensity (open label)
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to day 42
    End point values
    		 Rilonacept 160mg Rilonacept 320mg
    Number of subjects analysed
    9
    2
    Units: scores
        arithmetic mean (standard deviation)
    0.27 ( 2.28 )
    1.5 ( 2.12 )
    Statistical analysis title
    		 ACUSI open label
    Comparison groups
    Rilonacept 320mg v Rilonacept 160mg
    Number of subjects included in analysis
    11
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Mast cell mediator release in blood of CCU

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    End point title
    		 Mast cell mediator release in blood of CCU
    End point description
    During the course of the study, mast cell mediators were determined by cold water provocation at the end of the double-blind study phase and at the end of the study at V8. The mediators IL-1ra, IL-6, IL-18 and HSP70 were determined before the provocation with 4°C cold water as after the 5-minute provocation time and subsequently after 10 and 20 minutes. The IL1 receptor antibody could not be analyzed because the levels were below the detection level.
    End point type
    Secondary
    End point timeframe
    From V2-V5 plus open label V8 12 Weeks
    End point values
    		 Rilonacept 160mg Placebo
    Number of subjects analysed
    11
    9
    Units: Subjects
    11
    9
    Attachments
    		 Untitled (Filename: mastcell mediators.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Rilonacept 160mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Rilonacept 160mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Rilonacept 160mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 11 (90.91%)
    5 / 9 (55.56%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 11 (36.36%)
    3 / 9 (33.33%)
         occurrences all number
    4
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Injection related reaction
         subjects affected / exposed
    5 / 11 (45.45%)
    1 / 9 (11.11%)
         occurrences all number
    11
    1
    Infections and infestations
    Infection upper respiratory tract
         subjects affected / exposed
    5 / 11 (45.45%)
    3 / 9 (33.33%)
         occurrences all number
    5
    3
    urinary tract infection
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2017
    Sponsor`s substantial amendment code number, version, date for the clinical trial concerned: (CURES, Version 1, 06. December 2016) Change or addition of principal investigator(s),co-ordinating investigator addition of a new site

    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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