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    Clinical Trial Results:
    Tocilizumab for the Treatment of Familial Mediterranean Fever – A randomized, doubleblind, phase II proof of concept study-TOFFIFE

    Summary
    EudraCT number
    		 2016-004505-13
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TOFFIFE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03446209
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Tuebingen
    Sponsor organisation address
    Geissweg 3 , Tuebingen, Germany, 72076
    Public contact
    Department of Internal Medicine II, University Hospital Tuebingen, +49 7071292980681, joerg.henes@med.uni-tuebingen.de
    Scientific contact
    Department of Internal Medicine II, University Hospital Tuebingen, +49 7071292980681, joerg.henes@med.uni-tuebingen.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
    25 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Tocilizumab in patients with active FMF in a randomized, placebo controlled setting Efficacy: measured by Physician’s Global Assessment of disease activity (PGA) at week 16 Primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR and/or CRP (the one that led to inclusion must be normalized) + normalized SAA
    Protection of trial subjects
    The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation of this trial, are designed to ensure that all persons involved in the trial act according to Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the Declaration of Helsinki. This is a scientific clinical study; the German Medicines Act (AMG) §40 is applicable without restrictions according to section §42
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Apr 2018
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 An enrolment request for a patient will be sent from the site to the CI. After the CI has confirmed, that the subject can be enrolled, a unique subject number for identification purposes will be assigned to the patient in order to maintain his/her anonymity. The subject number will be used for the patient throughout the study.

    Pre-assignment
    Screening details
    		 Screening will be performed within 28 days prior to first administration of TCZ. The investigator will review all information obtained from the screening procedures and will inform the CI via an eligibility form. The CI will confirm, in writing, whether the subject fulfil all criteria for eligibility.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The i.v. medication/placebo will be prepared by an unblinded member of the study group at each center or by the local pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab arm
    Arm description
    		 Tocilizumab i.v. 8 mg/kg bodyweight (max. 800mg) infusion blinded by cover, every 4 weeks up to week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    RoAcemtra, Actemra
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tocilizumab i.v. 8 mg/kg bodyweight (max. 800mg) infusion blinded by cover, every 4 weeks up to week 24

    Arm title
    		 Placebo arm
    Arm description
    		 NaCl 0.9% infusion blinded by cover, every 4 weeks up to week 24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NaCl 0.9% infusion blinded by cover, every 4 weeks up to week 24.

    Number of subjects in period 1
    		Tocilizumab arm Placebo arm
    Started
    15
    15
    Completed
    13
    12
    Not completed
    2
    3
         Consent withdrawn by subject
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab arm
    Reporting group description
    		 Tocilizumab i.v. 8 mg/kg bodyweight (max. 800mg) infusion blinded by cover, every 4 weeks up to week 24.

    Reporting group title
    Placebo arm
    Reporting group description
    		 NaCl 0.9% infusion blinded by cover, every 4 weeks up to week 24.

    Reporting group values
    		 Tocilizumab arm Placebo arm Total
    Number of subjects
    		 15 15 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 15 15 30
    Age continuous
    Units: years
        median (full range (min-max))
    		 33 (18 to 53) 28.5 (18 to 41) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 8 8 16
    Disease duration
    Units: years
        median (full range (min-max))
    		 18 (2 to 44) 12.5 (0 to 29) -
    Baseline weight
    Units: kilogram(s)
        median (full range (min-max))
    		 70 (50 to 140) 70.5 (61 to 117) -
    Baseline height
    Units: centimetre
        median (full range (min-max))
    		 166 (150 to 180) 170 (159 to 183) -
    Baseline FFbH
    Hannover Functional Questionnaire Backache (FFbH-R) is a questionnaire for the diagnosis of functional disability caused by backache. German title: Funktionsfragebogen Hannover Rücken (FFbH-R)
    Units: percent
        median (full range (min-max))
    		 91.7 (66.7 to 100) 88.9 (8.3 to 100) -
    DAS28 Disease Score
    Units: points
        median (full range (min-max))
    		 3.4 (1.2 to 7.2) 3.2 (1.8 to 5.5) -
    Baseline VAS patient activity
    The visual analog scale for pain is a straight line with one end meaning no pain and the other end meaning the worst pain imaginable.
    Units: score
        median (full range (min-max))
    		 58 (15 to 88) 47 (0 to 77) -
    Baseline PGA (0-24)
    Units: points
        median (full range (min-max))
    		 10 (3 to 17) 8 (0 to 17) -
    Baseline SAA
    Serum amyloid A (SAA) is the most prominent acute phase reactant as its serum levels in acute phase response demonstrate the most notable increase
    Units: milligram(s)/litre
        median (full range (min-max))
    		 31 (1 to 661) 18 (3 to 275) -
    Baseline CRP
    C-Reactive Protein test measures the level of c-reactive protein (CRP) in your blood. It is seen as a biomarker for inflammation.
    Units: milligram(s)/decilitre
        median (full range (min-max))
    		 1.4 (0.0 to 15.3) 0.9 (0.2 to 4.2) -
    Baseline ESR
    The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour.
    Units: millimetre(s)
        median (full range (min-max))
    		 14 (4 to 65) 14 (0 to 41) -

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab arm
    Reporting group description
    		 Tocilizumab i.v. 8 mg/kg bodyweight (max. 800mg) infusion blinded by cover, every 4 weeks up to week 24.

    Reporting group title
    Placebo arm
    Reporting group description
    		 NaCl 0.9% infusion blinded by cover, every 4 weeks up to week 24.

    Primary: Number of patients reaching response to treatment

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    End point title
    		 Number of patients reaching response to treatment
    End point description
    The primary endpoint of the trial is to compare Tocilizumab and Placebo in terms of response to treatment. The number of patients reaching response to treatment will be documented for each treatment arm. It will be reached when the PGA < or = to 2, and normalization of SAA and CRP and/or ESR. 2 of the patients (15.4%) of the Tocilizumab arm reached the primary endpoint with a PGA< or equal to 2, normalization of SAA and CRP and/or ESR. None of the placebo arm patients reached the primary endpoint
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 Tocilizumab arm Placebo arm
    Number of subjects analysed
    13
    12
    Units: Subjects
    2
    0
    Statistical analysis title
    		 Statistical analysis of the primary endpoint
    Comparison groups
    Tocilizumab arm v Placebo arm
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.089
    Method
    		 Mantel-Haenszel
    Confidence interval
    Notes
    [1] - The proportion of patients who experienced the primary endpoint were compared and statistically assessed using a two sided Mantel-Haenszel chi-square test, stratified by centre, to test the null hypothesis of equal proportions in the two therapy groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Tocilizumab arm
    Reporting group description
    		 Tocilizumab i.v. 8 mg/kg bodyweight (max. 800mg) infusion blinded by cover, every 4 weeks up to week 24.

    Reporting group title
    Placebo arm
    Reporting group description
    		 NaCl 0.9% infusion blinded by cover, every 4 weeks up to week 24.

    Serious adverse events
    		 Tocilizumab arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Ileitis
    Additional description: Inflammation of the Ileum
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Severe disease activity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tocilizumab arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    8 / 12 (66.67%)
    Cardiac disorders
    Cardiac
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 12 (25.00%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Infection
         subjects affected / exposed
    10 / 13 (76.92%)
    5 / 12 (41.67%)
         occurrences all number
    10
    5
    FMF flare
         subjects affected / exposed
    10 / 13 (76.92%)
    4 / 12 (33.33%)
         occurrences all number
    10
    4
    Gastrointestinal disorders
    Gastroenterology
         subjects affected / exposed
    9 / 13 (69.23%)
    2 / 12 (16.67%)
         occurrences all number
    9
    2
    Hepatobiliary disorders
    Increased liver enzymes
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    6 / 13 (46.15%)
    2 / 12 (16.67%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Joint complaint
         subjects affected / exposed
    6 / 13 (46.15%)
    1 / 12 (8.33%)
         occurrences all number
    6
    1

    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.
    Due to insufficient response or side effects, seven (28%) of patients terminated earlier than week 16, which led to missing data at week 16. These early terminations occurred in 4 (33.3%) patients of the placebo arm and in 3 (23.1%) in the TCZ arm.
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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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