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    Clinical Trial Results:
    Exercise-induced cardiac adaptions in rheumatoid arthritis patients during interleukin-6 vs. tumor necrosis factor antibody therapy: a randomised controlled study (RABEX).

    Summary
    EudraCT number
    		 2021-005287-21
    Trial protocol
    		 DK  
    Global end of trial date
    03 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jan 2025
    First version publication date
    25 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Simon1234
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05215509
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Center for Aktiv Sundhed, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark,
    Public contact
    Simon Jønck, Rigshospitalet, Center for Aktiv Sundhed, simon.joenck.04@regionh.dk
    Scientific contact
    Simon Jønck, Rigshospitalet, Center for Aktiv Sundhed, simon.joenck.04@regionh.dk
    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
    17 Jan 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this study (RABEX) is to investigative the physiological effects of the cytokines IL-6 and TNF on the adaptive changes to exercise in patients with rheumatoid arthritis. We will compare rheumatoid arthritis patients in treatment with either IL-6 or TNF blockage on exercise-induced cardiac adaptations as well as metabolic adaptations including oral glucose tolerance test (OGTT) and changes in adipose tissue mass.
    Protection of trial subjects
    All subjects underwent standard care at out-patient clinics independent of this study. All subjects were assessed by experienced physicians at baseline. All MRI scans performed were analyzed by experts in the field.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jan 2022
    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
    Denmark: 69
    Worldwide total number of subjects
    69
    EEA total number of subjects
    69
    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)
    65
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited by either 1) Direct information from a nurse at a collaborating out-patient clinic or 2) by mail

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 69
    Number of subjects completed
    		 69

    Period 1
    Period 1 title
    Intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Investigator, Monitor, Data analyst, Assessor [2]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (IL-6 inhibitor group)
    Arm description
    		 Subjects in stable IL-6 inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kevzara
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    200 mg / 2 weeks (standard dose) Subjects in the Intervention (IL-6 inhibitor group) did not exclusively undergo treatment with Kevzara as an IL-6 inhibitor. Kevzara was chosen as a representative for the family of drugs inhibiting IL-6.

    Arm title
    		 Intervention (TNF inhibitor group)
    Arm description
    		 Subjects in stable TNF inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amgevita
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg / 2 weeks (standard dose) Subjects in the Intervention (TNF inhibitor group) did not exclusively undergo treatment with Amgevita as an TNF inhibitor. Amgevita was chosen as a representative for the family of drugs inhibiting TNF.

    Arm title
    		 Control (IL-6 inhibitor group)
    Arm description
    		 Subjects in stable IL-6 inhibitor treatment randomized to no supervised exercise (standard of care/control)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Control (TNF inhibitor group)
    Arm description
    		 Subjects in stable TNF inhibitor treatment randomized to no supervised exercise (standard of care/control)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: This was an open-label exercise intervention trial. Subjects could not be blinded to the intervention (exercise) or control (no exercise). Investigators and data analysts were blinded to the intervention.
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This was an open-label exercise intervention trial. Subjects could not be blinded to the intervention (exercise) or control (no exercise). Investigators and data analysts were blinded to the intervention.
    Number of subjects in period 1
    		Intervention (IL-6 inhibitor group) Intervention (TNF inhibitor group) Control (IL-6 inhibitor group) Control (TNF inhibitor group)
    Started
    17
    20
    12
    20
    Completed
    12
    20
    11
    18
    Not completed
    5
    0
    1
    2
         Lost to follow-up
    5
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention (IL-6 inhibitor group)
    Reporting group description
    		 Subjects in stable IL-6 inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)

    Reporting group title
    Intervention (TNF inhibitor group)
    Reporting group description
    		 Subjects in stable TNF inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)

    Reporting group title
    Control (IL-6 inhibitor group)
    Reporting group description
    		 Subjects in stable IL-6 inhibitor treatment randomized to no supervised exercise (standard of care/control)

    Reporting group title
    Control (TNF inhibitor group)
    Reporting group description
    		 Subjects in stable TNF inhibitor treatment randomized to no supervised exercise (standard of care/control)

    Reporting group values
    		 Intervention (IL-6 inhibitor group) Intervention (TNF inhibitor group) Control (IL-6 inhibitor group) Control (TNF inhibitor group) Total
    Number of subjects
    		 17 20 12 20 69
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 16 19 11 19 65
        From 65-84 years
    		 1 1 1 1 4
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.9 ( 7.1 ) 51.3 ( 10.9 ) 52.8 ( 10.4 ) 54.7 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 16 10 16 56
        Male
    		 3 4 2 4 13

    End points

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    End points reporting groups
    Reporting group title
    Intervention (IL-6 inhibitor group)
    Reporting group description
    		 Subjects in stable IL-6 inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)

    Reporting group title
    Intervention (TNF inhibitor group)
    Reporting group description
    		 Subjects in stable TNF inhibitor treatment randomized to supervised exercise (3 session/week for 12 weeks)

    Reporting group title
    Control (IL-6 inhibitor group)
    Reporting group description
    		 Subjects in stable IL-6 inhibitor treatment randomized to no supervised exercise (standard of care/control)

    Reporting group title
    Control (TNF inhibitor group)
    Reporting group description
    		 Subjects in stable TNF inhibitor treatment randomized to no supervised exercise (standard of care/control)

    Primary: Change in left ventricular mass

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    End point title
    		 Change in left ventricular mass
    End point description
    Measured by MRI
    End point type
    Primary
    End point timeframe
    Change from baseline to follow-up (12 weeks)
    End point values
    		 Intervention (IL-6 inhibitor group) Intervention (TNF inhibitor group) Control (IL-6 inhibitor group) Control (TNF inhibitor group)
    Number of subjects analysed
    17
    20
    12
    20
    Units: gram(s)
        least squares mean (confidence interval 95%)
    2.7 (-0.4 to 5.8)
    3.9 (1.1 to 6.8)
    1.4 (-2.0 to 4.9)
    0.1 (-2.9 to 3.1)
    Statistical analysis title
    		 Interaction analysis primary endpoint
    Comparison groups
    Intervention (IL-6 inhibitor group) v Intervention (TNF inhibitor group) v Control (IL-6 inhibitor group) v Control (TNF inhibitor group)
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - p-value for the interaction analysis between IL-6 inhibtor treatment and exercise on changes to left ventricular mass following a 12 week exercise intervention compared to TNF inhibitor treatment, relative to control

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Follow-up (12 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Intervention (IL-6 inhibitor group)
    Reporting group description
    		 -

    Reporting group title
    Intervention (TNF inhibitor group)
    Reporting group description
    		 -

    Reporting group title
    Control (IL-6 inhibitor group)
    Reporting group description
    		 -

    Reporting group title
    Control (TNF inhibitor group)
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention (IL-6 inhibitor group) Intervention (TNF inhibitor group) Control (IL-6 inhibitor group) Control (TNF inhibitor group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Intervention (IL-6 inhibitor group) Intervention (TNF inhibitor group) Control (IL-6 inhibitor group) Control (TNF inhibitor group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    18 / 20 (90.00%)
    8 / 12 (66.67%)
    18 / 20 (90.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Other
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 20 (20.00%)
    1 / 12 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    2
    4
    1
    2
    Musculoskeletal and connective tissue disorders
    Lower extremities
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 20 (15.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    4
    3
    1
    1
    Upper extremities
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    2
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Other
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    1
    2
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    4 / 17 (23.53%)
    2 / 20 (10.00%)
    1 / 12 (8.33%)
    3 / 20 (15.00%)
         occurrences all number
    4
    2
    1
    3
    Viral infection
         subjects affected / exposed
    5 / 17 (29.41%)
    6 / 20 (30.00%)
    3 / 12 (25.00%)
    5 / 20 (25.00%)
         occurrences all number
    5
    6
    3
    5
    Other
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2021
    One inclusion criteria was changed from latest Clinical Disease Activity Index <= 2.8 to Disease Activity Score-28-ESR <= 3.2

    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
    For support, Contact us.
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    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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