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    Clinical Trial Results:
    Factor XII-associated cold autoinflammatory syndrome (FACAS) linked tokallikrein-kinin pathology: Proof of concept treatment with Lanadelumab (DX-2930) Short title: LANA-FXII

    Summary
    EudraCT number
    		 2019-001235-31
    Trial protocol
    		 DE  
    Global end of trial date
    10 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jan 2026
    First version publication date
    15 Jan 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DEALSZ-2019-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Karoline Krause, Institute of Allergology, Campus Benjamin Franklin, 0049 30450518043, ifa@charite.de
    Scientific contact
    Karoline Krause, Institute of Allergology, Campus Benjamin Franklin, 0049 30450518043, ifa@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
    14 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jun 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of Lanadelumab on the clinical signs and symptoms of FXII-associated cold autoinflammatory syndrome (reduction in symptomatic days with urticarial rash, arthralgia, headache, chills)
    Protection of trial subjects
    The study was conducted in accordance with the ICH E6 (R2) Guideline for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, German Medicinal Products Act (AMG)), and with the ethical principles that have their origins in the Declaration of Helsinki (version 2013).
    Background therapy
    		 Factor XII is a serine protease with diverse functions that participates in coagulation, fibrinolysis, complement, and contact system activation. So far, mutations in the factor XII gene have been linked to the rare coagulation disorder Hagemann factor deficiency and hereditary angioedema (FXII-HAE). We recently identified a novel Factor FXII (FXII) mutation in a 4-generation family with an autoinflammatory clinical phenotype. Affected family members show severe cold-associated symptoms (urticarial rash, chills, joint and bone pain, headache, fatigue), that worsen with age and partially respond to IL-1 receptor antagonist anakinra. Genetic analysis revealed no pathogenic mutations in classic autoinflammatory genes such as NLRP3, NLRP12, or others; however, we observed a novel heterozygous mutation affecting the FXII-kallikrein-kinin pathway. Neither angioedema attacks nor coagulation disorders were reported. In all affected family members, plasma levels of FXIIa were upregulated, and prekallikrein consecutively downregulated. Lanadelumab is a fully human, monoclonal antibody (IgG1/ κ-light chain) that inhibits active plasma kallikrein proteolytic activity, providing sustained control of plasma kallikrein activity and thereby limiting bradykinin generation. The primary objective of this study was to assess the effect of Lanadelumab on the clinical signs and symptoms (patient-reported disease activity) of FACAS. Thus, the change in patient reported disease activity total score (mean of weeks 9 to 12 compared to mean of weeks -4 to -1 (baseline)) was determined as the primary endpoint. In addition, the effect of Lanadelumab on inflammation markers (such as CRP, ESR, SAA, S100A8/9), as well as on patients´ quality of life, was aimed to be investigated.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 2020
    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: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    1
    Adults (18-64 years)
    2
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at one site at Charité.

    Pre-assignment
    Screening details
    		 Four persons were assessed for eligibility (screened), no re-screening was necessary. All 4 of them were enrolled in the study and were allocated to the treatment intervention and received the IMP.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    this study was planned and conducted as an open-label, singlearm trial

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanadelumab
    Investigational medicinal product code
    CAS Number 1426055-14-2
    Other name
    Takzhyro
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received an injection of 300 mg Lanadelumab every 2 weeks.

    Number of subjects in period 1
    		Treatment
    Started
    4
    Completed
    4

    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
    		 4 4
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 2 2
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Primary: Change in patient-reported disease activity (PR-DA)

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    End point title
    		 Change in patient-reported disease activity (PR-DA) [1]
    End point description
    Analysis of efficacy: The PR-DA total score declined from a mean value of 15.47 (SD = 5.92) at baseline (weeks -4 to -1), to a mean value of 3.60 (SD = 7.16) at weeks 9 to 12. This is a change of -11.87 units (SD = 4.70, p-value = 0.050).
    End point type
    Primary
    End point timeframe
    from baseline up to 12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A limitation of the study is the small sample size of n=4. No statistical analysis for the primary endpoint was conducted.
    End point values
    		 Treatment
    Number of subjects analysed
    4
    Units: score
    arithmetic mean (standard deviation)
        baseline (weeks -4 to -1)
    15.47 ( 5.92 )
        weeks 9 -12
    3.6 ( 7.16 )
    Attachments
    		 charts_primary and secondary endpoints
    No statistical analyses for this end point

    Secondary: Change in PR-DA total score at weeks 24 to 28

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    End point title
    		 Change in PR-DA total score at weeks 24 to 28
    End point description
    Analysis of efficac The PR-DA total score declined from a mean value of 15.47 (SD = 5.92) at baseline (weeks -4 to -1), to a mean value of 1.65 (SD = 3.30) at weeks 25 to 28. This is a change of -13.82 units (SD = 4.03, p-value = 0.050). P
    End point type
    Secondary
    End point timeframe
    from baseline to weeks 24-28
    End point values
    		 Treatment
    Number of subjects analysed
    4
    Units: score
    arithmetic mean (standard deviation)
        baseline
    15.47 ( 5.92 )
        weeks 24-28
    1.65 ( 3.3 )
    No statistical analyses for this end point

    Secondary: Change in PR-DA urticarial rash score

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    End point title
    		 Change in PR-DA urticarial rash score
    End point description
    The PR-DA Urticarial Rash Score declined from a mean value of 3.92 (SD = 1.34) at baseline (weeks -4 to -1), over a mean value of 0.00 (SD = 0.00) at weeks 9 to 12, to a mean value of 0.00 (SD = 0.00) at weeks 25 to 28. This is a change of -3.92 units (SD = 1.34, p-value = 0.050) from baseline to weeks 9 to 12, versus a change of -3.92 units (SD = 1.34, p-value = 0.050) from baseline to weeks 25 to 28.
    End point type
    Secondary
    End point timeframe
    from baseline up to week 28
    End point values
    		 Treatment
    Number of subjects analysed
    4
    Units: score
    arithmetic mean (standard deviation)
        weeks 9 to 12
    0 ( 0 )
        weeks 25 to 28
    0 ( 0 )
        baseline
    3.92 ( 1.34 )
    No statistical analyses for this end point

    Secondary: Change in PR-DA fatigue score

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    End point title
    		 Change in PR-DA fatigue score
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to 28 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    4
    Units: score
    arithmetic mean (standard deviation)
        baseline
    3.88 ( 1.39 )
        weeks 9 to 12
    1.4 ( 2.81 )
        weeks 25 to 28
    0.59 ( 1.18 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    treatment
    Reporting group description
    		 -

    Serious adverse events
    		 treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    Injury, poisoning and procedural complications
    Pansynovitis with secondary bleeding
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site urticaria
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2019
    update protocol version 1.1 • Additional information was added to background and overall study rationale
    04 Dec 2019
    update protocol version 1.2: • Changes in Information on contraception
    07 Dec 2022
    update protocol 1.3: • Inclusion of Adolescents
    15 Aug 2023
    update protocol 2.0: • Adjustment of applicable legislation (no reference to US law) • Adaptation of administrative structure • Update of Database Management and Quality Control (section 10.4) as well as Data Analysis (section 11) – paper CRF and SPSS will be used

    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.
    A limitation of the study is the small sample size of n=4. Based on the results of the study, Lanadelumab may be considered as an effective treatment option in FACAS patients.
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    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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