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    Clinical Trial Results:
    Sequential B cell/T cell therapy to re-induce humoral immune tolerance in ACPA-positive Rheumatoid Arthritis (TOLERA): a prospective randomized controlled open-label single-centre clinical trial in adult subjects with active ACPA-positive Rheumatoid Arthritis failing Methotrexate

    Summary
    EudraCT number
    		 2018-003877-91
    Trial protocol
    		 DE  
    Global end of trial date
    28 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2024
    First version publication date
    22 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TOLERA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Erlangen
    Sponsor organisation address
    Maximiliansplatz 2, Erlangen, Germany, 91054
    Public contact
    Medizinische Klinik 3, Universitätsklinikum Erlangen, arnd.kleyer@extern.uk-erlangen.de
    Scientific contact
    Medizinische Klinik 3, Universitätsklinikum Erlangen, arnd.kleyer@extern.uk-erlangen.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
    23 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of a sequential Rituximab/Abatacept treatment on auto-antibody production and thereby determine its potential to lower ACPA levels and to induce a potential seroconversion and thus an immunological remission
    Protection of trial subjects
    Vigorous inclusion and exclusion criteria; close monitoring visits for patients on drug
    Background therapy
    		 Methotrexate (maximal tolerated dose, range 0-25 mg/week)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2019
    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)
    15
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient recruitment was performed in the outpatient and inpatient ward of the department of Internal Medicine 3, Universitätsklinikum Erlangen

    Pre-assignment
    Screening details
    		 ACR-EULAR criteria of Rheumatoid Arthritis fulfilled, SDAI >= 11, ACPA positive, inadequate treatment response / intolerance to cDMARDs or bDMARDs

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab + best medical care
    Arm description
    		 Control group: rituximab 1000 mg week 0 and week 2 i.v., followed by best medical care until week 52
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg i.v. at week 0 and week 2

    Arm title
    		 Rituximab + Abatacept
    Arm description
    		 Treatment group: rituximab 1000 mg week 0 and week 2 i.v., followed by abatacept 125 mg s.c. from week 8 until week 52 once weekly (44 weeks)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg i.v. at week 0 and week 2

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    125 mg s.c. once weekly from week 8 until week 52 (44 weeks)

    Number of subjects in period 1
    		Rituximab + best medical care Rituximab + Abatacept
    Started
    10
    10
    Completed
    9
    9
    Not completed
    1
    1
         worsening of disease
    1
    -
         incompliance
    -
    1

    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
    		 20 20
    Age categorical
    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 (full range (min-max))
    		 53.2 (22 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 11 11
    Disease duration
    Units: year
        arithmetic mean (full range (min-max))
    		 7.8 (1 to 39) -
    ACPA level
    Units: unit(s)/millilitre
        arithmetic mean (standard deviation)
    		 252.7 ( 341.8 ) -
    SDAI
    Units: none
        arithmetic mean (standard deviation)
    		 24.6 ( 10.9 ) -
    CDAI
    Units: none
        arithmetic mean (standard deviation)
    		 22.2 ( 9.2 ) -
    DAS-28 ESR
    Units: none
        arithmetic mean (standard deviation)
    		 4.8 ( 1.4 ) -
    DAS-28 CRP
    Units: none
        arithmetic mean (standard deviation)
    		 4.6 ( 1.1 ) -
    CRP
    Units: milligram(s)/litre
        arithmetic mean (standard deviation)
    		 24.4 ( 40.8 ) -
    ESR
    Units: millimetre(s)/hour
        arithmetic mean (standard deviation)
    		 29.7 ( 25.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab + best medical care
    Reporting group description
    		 Control group: rituximab 1000 mg week 0 and week 2 i.v., followed by best medical care until week 52

    Reporting group title
    Rituximab + Abatacept
    Reporting group description
    		 Treatment group: rituximab 1000 mg week 0 and week 2 i.v., followed by abatacept 125 mg s.c. from week 8 until week 52 once weekly (44 weeks)

    Primary: Proportion of anti CCP2 antibody seroconversions

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    End point title
    		 Proportion of anti CCP2 antibody seroconversions [1]
    End point description
    defined as lowering of anti-CCP2 antibodies below 5 RE/ml
    End point type
    Primary
    End point timeframe
    week 52
    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: descriptive analysis
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Change in anti CCP2 antibody levels

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    End point title
    		 Change in anti CCP2 antibody levels
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: unit(s)/millilitre
        arithmetic mean (confidence interval 95%)
    -71.03 (-157.09 to -12.25)
    -2.83 (-67.58 to 60.35)
    No statistical analyses for this end point

    Secondary: Change in IgA

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    End point title
    		 Change in IgA
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: milligram(s)/dl
        arithmetic mean (confidence interval 95%)
    -31.07 (-60.27 to -7.73)
    34.60 (0.51 to 69.94)
    No statistical analyses for this end point

    Secondary: Change in IgG

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    End point title
    		 Change in IgG
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: millligram(s)/dl
        arithmetic mean (confidence interval 95%)
    -34.31 (-85.02 to 19.30)
    49.01 (-53.88 to 167.61)
    No statistical analyses for this end point

    Secondary: Change in IgM

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    End point title
    		 Change in IgM
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: milligram(s)/dl
        arithmetic mean (confidence interval 95%)
    -34.46 (-78.65 to -3.59)
    -12.09 (-27.41 to 1.25)
    No statistical analyses for this end point

    Secondary: Change in number of CCP+ B Cells

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    End point title
    		 Change in number of CCP+ B Cells
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: /millilitre
        arithmetic mean (confidence interval 95%)
    -15.11 (-26.89 to -2.22)
    -5.80 (-30.20 to 15.40)
    No statistical analyses for this end point

    Secondary: Change in SDAI

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    End point title
    		 Change in SDAI
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: none
        arithmetic mean (confidence interval 95%)
    -13.64 (-21.69 to -5.66)
    -16.70 (-23.38 to -9.59)
    No statistical analyses for this end point

    Secondary: Change in CDAI

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    End point title
    		 Change in CDAI
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: none
        arithmetic mean (confidence interval 95%)
    -11.36 (-17.87 to -5.01)
    -16.47 (-23.06 to -8.71)
    No statistical analyses for this end point

    Secondary: Change in DAS28 (CRP)

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    End point title
    		 Change in DAS28 (CRP)
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: none
        arithmetic mean (confidence interval 95%)
    -1.38 (-2.03 to -0.79)
    -1.88 (-2.68 to -1.04)
    No statistical analyses for this end point

    Secondary: Change in DAS28 (ESR)

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    End point title
    		 Change in DAS28 (ESR)
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 compared to baseline
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: none
        arithmetic mean (confidence interval 95%)
    -1.57 (-2.24 to -0.90)
    -1.74 (-2.54 to -0.93)
    No statistical analyses for this end point

    Secondary: DAS28 remission

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    End point title
    		 DAS28 remission
    End point description
    number of patients in DAS28 remission at week 52
    End point type
    Secondary
    End point timeframe
    week 52
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: subjects
    2
    2
    No statistical analyses for this end point

    Secondary: SDAI remission

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    End point title
    		 SDAI remission
    End point description
    number of patients in SDAI remission at week 52
    End point type
    Secondary
    End point timeframe
    week 52
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: subject
    0
    3
    No statistical analyses for this end point

    Secondary: Boolean remission

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    End point title
    		 Boolean remission
    End point description
    number of patients in Boolean remission at week 52
    End point type
    Secondary
    End point timeframe
    week 52
    End point values
    		 Rituximab + best medical care Rituximab + Abatacept
    Number of subjects analysed
    9
    9
    Units: subject
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    V1 (enrolment) - V9 (EoS)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    All subjects enrolled
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects enrolled
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 20 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    hand fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shoulder operation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All subjects enrolled
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin lesion removal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tendon operation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth extraction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Impaired healing
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Throat tightness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Listless
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Eye injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hand fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Meniscus injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tibia fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diverticulum
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blister
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Bursitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Enthesopathy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    COVID-19
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Fungal infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2019
    anti-CCP2 antibody test system changed
    15 Apr 2020
    Clarification: in case of MTX intolerance Rituximab / Abatacept can be used as monotherapy

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Apr 2020
    Recruitment stop due to COVID-19 pandemia
    04 May 2020

    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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