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    Clinical Trial Results:
    Disease activity-guided tapering of biologics in patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis: The pragmatic, multi-centre, randomized, open-label, equivalence BIOlogical Dose OPTimisation (BIODOPT) trial

    Summary
    EudraCT number
    		 2017-001970-41
    Trial protocol
    		 DK  
    Global end of trial date
    19 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Dec 2025
    First version publication date
    10 Dec 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20170508
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital, Department of Rheumatology
    Sponsor organisation address
    Reberbansgade 15, Aalborg, Denmark, 9000
    Public contact
    MD, PhD Line Uhrenholt, Aalborg University Hospital, Department of Rheumatology, +45 21707727, l.uhrenholt@rn.dk
    Scientific contact
    MD, PhD Line Uhrenholt, Aalborg University Hospital, Department of Rheumatology, +45 21707727, l.uhrenholt@rn.dk
    Sponsor organisation name
    Aalborg University Hospital, Department of Rheumatology
    Sponsor organisation address
    Reberbansgade 15, Aalborg, Denmark, 9000
    Public contact
    MD, PhD Salome Kristensen , Aalborg University Hospital, Department of Rheumatology , +45 97664015, sakr@rn.dk
    Scientific contact
    MD, PhD Salome Kristensen , Aalborg University Hospital, Department of Rheumatology , +45 97664015, sakr@rn.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
    20 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The BIODOPT trial compares a disease activity-guided tapering algorithm to continuation of biologics as usual care in patients with inflammatory arthritis in sustained low disease activity. The co-primary objective was met if superiority in the proportion of patients achieving ≥50% biologic redudtion at 18 months was demonstrated while mean disease activity remained equivalent, an equivalence margin of ± 0.5 disease activity points was pre-specified.
    Protection of trial subjects
    Trial subjects were monitored at the rheumatology out patient clinic at baseline, month 4, month 8, month 12, month 18, and month 24. Furthermore, a long-term assessment at year 5 was conducted. Between year 2 and year 5, patients were monitored in accordance with national guidelines i.e., yearly or after the treating rheumatologist discretion.
    Background therapy
    		 At baseline, concomitant csDMARDs were used by 43% of the tapering group and 47% of the control grup - the majority was MTX (42% vs 43%, respectively).
    Evidence for comparator
    		 Biological therapies and disease activity-guided monitoring have improved the management of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA), as large proportions of patients reach low disease activity (LDA). But increasing evidence suggest that patients can maintain disease control even if the biological therapies are tapred. In clinical trials, biologic tapering is done by either a fixed dose reduction, often in one step, e.g. 50% interval prolongation/dose reduction, or disease activity-guided tapering after an algorithm until flare or withdrawal. Disease activity-guided tapering of biologics is generally the more aggressive approach as it allows maximal tapering. Evidence on disease activity-guided tapering of biologics vs continuation of biologics as usual care is limited to a few randomized controlled trials.
    Actual start date of recruitment
    17 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 142
    Worldwide total number of subjects
    142
    EEA total number of subjects
    142
    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)
    103
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eligble patients recieved information about the trial at rutine visits in the Rheumatology outpatient clinic. Patients who wished to participate were enrolled after writen informed consent were provided. The inclusion period started in May 2018 and ended pre-maturely in April 2020 because of the national implications of the COVID-19 pandemic.

    Pre-assignment
    Screening details
    		 Eligible patients were adults diagnosed with RA, PsA, or axSpA in LDA and treated with abatacept, adalimumab, certolizumab-pegol, etanercept, golimumab, infliximab, or tocilizumab, including biosimilars, on a stable dosage for ≥ 12 months. Glucocorticoids (oral, intramuscular, or intraarticular) within the past 12 months were not allowed.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The interventions in this trial were not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 The tapering group
    Arm description
    		 The tapering group followed a disease activity-guided tapering strategy for the biological therapy, i.e., the biologic dosing interval was prolonged by approximately 25% every 4 months until flare or complete biological withdrawal.However, due to the longer dosing interval for infliximab, it was decided to space the infliximab dosing interval by 2 weeks at each infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    L04AA24
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection, Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Injection , Concentrate for solution for infusion
    Dosage and administration details
    Subcutaneous injections: 125 mg every week Intravenous infusions: - Weight < 60 kg: 500 mg every 4 weeks - Weight 60-100 kg: 750 mg every 4 weeks - Weight > 100 kg: 1000 mg every 4 week

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    L04AB04
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 40 mg every 2 weeks

    Investigational medicinal product name
    Certolizumab-pegol
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: - 200 mg subcutaneous every 2 weeks OR - 400 mg subcutaneous every 4 week

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    L04AB01
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 50 mg every week

    Investigational medicinal product name
    Golimumab
    Investigational medicinal product code
    L04AB06
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 50 mg every 4 weeks

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    L04AB02
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    - RA: 6 mg/kg intravenous every 8 weeks - PsA: 5 mg/kg intravenous every 8 weeks - AxSpA: 5 mg/kg intravenous every 6 weeks

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    L04AC07
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Concentrate and solvent for dispersion for injection
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    - Subcutaneous: 162 mg every week - Intravenous: 8 mg/kg every 4 weeks

    Arm title
    		 The Control group
    Arm description
    		 A pragmatic usual care practice was applied to the control group, i.e. the control group continued their baseline biological dosing interval unchanged but, if requested by the patient, a small increase of the dosing interval was allowed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    L04AA24
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Concentrate and solvent for dispersion for injection
    Routes of administration
    Concentrate for solution for infusion , Injection
    Dosage and administration details
    Subcutaneous injections: 125 mg every week Intravenous infusions: - Weight < 60 kg: 500 mg every 4 weeks - Weight 60-100 kg: 750 mg every 4 weeks - Weight > 100 kg: 1000 mg every 4 week

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    L04AB04
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 40 mg every 2 weeks

    Investigational medicinal product name
    Certolizumab-pegol
    Investigational medicinal product code
    L04AB05
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: - 200 mg subcutaneous every 2 weeks OR - 400 mg subcutaneous every 4 week

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    L04AB01
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 50 mg every week

    Investigational medicinal product name
    Golimumab
    Investigational medicinal product code
    L04AB06
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous: 50 mg every 4 weeks

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    L04AB02
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    - RA: 6 mg/kg intravenous every 8 weeks - PsA: 5 mg/kg intravenous every 8 weeks - AxSpA: 5 mg/kg intravenous every 6 weeks

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    L04AC07
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Concentrate and solvent for dispersion for injection
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    - Subcutaneous: 162 mg every week - Intravenous: 8 mg/kg every 4 weeks

    Number of subjects in period 1
    		The tapering group The Control group
    Started
    95
    47
    Completed
    88
    46
    Not completed
    7
    1
         Consent withdrawn by subject
    4
    -
         Adverse event, non-fatal
    -
    1
         Non-compliance to visits
    2
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    The tapering group
    Reporting group description
    		 The tapering group followed a disease activity-guided tapering strategy for the biological therapy, i.e., the biologic dosing interval was prolonged by approximately 25% every 4 months until flare or complete biological withdrawal.However, due to the longer dosing interval for infliximab, it was decided to space the infliximab dosing interval by 2 weeks at each infusion.

    Reporting group title
    The Control group
    Reporting group description
    		 A pragmatic usual care practice was applied to the control group, i.e. the control group continued their baseline biological dosing interval unchanged but, if requested by the patient, a small increase of the dosing interval was allowed.

    Reporting group values
    		 The tapering group The Control group Total
    Number of subjects
    		 95 47 142
    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 (standard deviation)
    		 51.9 ( 15.4 ) 52.3 ( 15.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 52 20 72
        Male
    		 43 27 70
    Diagnosis
    Units: Subjects
        RA
    		 41 20 61
        PsA
    		 18 8 26
        AxSpA
    		 36 19 55
    Smoking
    Units: Subjects
        Smoking
    		 15 9 24
        Not smoking
    		 80 38 118
    Disease activity
    Units: Subjects
        In remission
    		 82 40 122
        In LDA
    		 13 7 20
    On csDMARDs
    Units: Subjects
        On csDMARDs
    		 41 22 63
        Not on csDMARDs
    		 54 25 79
    On combination csDMARDs
    Units: Subjects
        On combination csDMARDs
    		 2 2 4
        Not on combination csDMARDs
    		 93 45 138
    On MTX
    Units: Subjects
        On MTX
    		 40 20 60
        Not on MTX
    		 55 27 82
    Baseline biological therapy
    Units: Subjects
        Abatacept
    		 1 3 4
        TNFi
    		 88 41 129
        Tocilizumab
    		 6 3 9
    Repeated biological failure
    On biological agent number three or higher
    Units: Subjects
        Repeated biological failure
    		 6 3 9
        No repeated biological failure
    		 89 44 133
    BMI
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 25.3 (23.2 to 29.2) 26.6 (23.1 to 29.4) -
    Disease duration
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 11.3 (6.3 to 17.9) 12.4 (6.4 to 19.9) -
    HAQ-DI
    Scale: 0.0-3.0
    Units: units
        median (inter-quartile range (Q1-Q3))
    		 0.13 (0.00 to 0.63) 0.13 (0.00 to 0.50) -
    Pain VAS
    Scale: 0-100 mm
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 10.0 (2.0 to 17.0) 11.0 (5.0 to 21.0) -
    Fatigue VAS
    Scale: 0-100 mm
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 16.0 (4.0 to 34.0) 25.0 (10.0 to 42.0) -
    Patient Global Health VAS
    Scale: 0-100 mm.
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 10.0 (2.0 to 21.0) 14.0 (5.0 to 28.0) -
    SF-36 PCS
    Short Form Health Survey 36 Physical Component Summary. Scale: 0-100.
    Units: units
        median (inter-quartile range (Q1-Q3))
    		 52.0 (47.4 to 55.1) 49.8 (44.2 to 52.6) -
    Tender joint count
    0-68 joints.
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -
    Swollen joint count
    0-66 joints.
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -
    CRP
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 2.6 (0.8 to 3.9) 2.2 (0.6 to 3.9) -
    Physician Global Health VAS
    Scale: 0-100 mm.
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -
    Disease activity score
    Evaluated using mixed model statistics with disease activity evaluated by DAS28-CRP for RA and PsA and ASDAS for axSpA.
    Units: points
        least squares mean (standard deviation)
    		 1.47 ( 0.50 ) 1.51 ( 0.50 ) -
    Duration of baseline biological therapy
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 5.1 (2.3 to 8.2) 4.2 (2.7 to 10.6) -

    End points

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    End points reporting groups
    Reporting group title
    The tapering group
    Reporting group description
    		 The tapering group followed a disease activity-guided tapering strategy for the biological therapy, i.e., the biologic dosing interval was prolonged by approximately 25% every 4 months until flare or complete biological withdrawal.However, due to the longer dosing interval for infliximab, it was decided to space the infliximab dosing interval by 2 weeks at each infusion.

    Reporting group title
    The Control group
    Reporting group description
    		 A pragmatic usual care practice was applied to the control group, i.e. the control group continued their baseline biological dosing interval unchanged but, if requested by the patient, a small increase of the dosing interval was allowed.

    Primary: Reduced to 50% or less of their baseline biological dosing

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    End point title
    		 Reduced to 50% or less of their baseline biological dosing
    End point description
    Part one of the co-primary endpoint was met if superiority in the proportion of patients achieving ≥50% biologic reduction at 18 months was demonstrated.
    End point type
    Primary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 1
        ≥50% biologic reduction
    35
    1
        <50% biologic reduction
    60
    46
    Statistical analysis title
    		 Statistical analysis plan for primary outcome 1A
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.45

    Primary: Disease activity score

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    End point title
    		 Disease activity score
    End point description
    Disease activity assessed 18 months from baseline (part two of the co-primary objective)
    End point type
    Primary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    1.84 ( 0.15 )
    1.75 ( 0.16 )
    Statistical analysis title
    		 Statistical analysis plan for primary objective 1B
    Statistical analysis description
    Analysis was performed and reported in accordance with the prespecified statistical analysis plan and the CONSORT statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Repeated measures, linear mixed-effects models were applied to evaluate contrasts between groups for continuous outcomes. The fixed factors were group, diagnosis, biologics failure history, centre, time-point, and the interaction (group x time).
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.29
    Notes
    [1] - The initiating investigators pre-specified a margin of equivalence at ±0.5 DAS28crp points for patients with RA or PsA and ±0.5ASDAS points for patients with axSpA. This margin was determined based on ‘less than half of the effect’ that would be considered a clinically relevant reduction in DAS28crp level (∆DAS28crp>1.2) or ASDAS level (∆ASDAS >1.1) corresponding to a clinically unimportant change in arthritis activity.

    Secondary: In remission

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    End point title
    		 In remission
    End point description
    Patients in remission measured by DAS28-CPR (RA and PsA) or ASDAS (axSpA)
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 1
        In remission
    63
    33
        Not in remission
    32
    14
    Statistical analysis title
    		 SAP remission
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.12

    Secondary: In low disease activity

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    End point title
    		 In low disease activity
    End point description
    In LDA evaluated by DAS28-CRP (RA and PsA) or ASDAS (axSpA).
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 1
        In LDA
    79
    41
        Not in LDA
    16
    6
    Statistical analysis title
    		 SAP LDA
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.08

    Secondary: ∆HAQ-DI

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    End point title
    		 ∆HAQ-DI
    End point description
    Change in HAQ-DI from baseline to month 18
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.01
        least squares mean (standard error)
    0.06 ( 0.06 )
    0.00 ( 0.07 )
    Statistical analysis title
    		 SAP HAQ-DI
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the CONSORT statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Repeated measures, linear mixed-effects models were applied to evaluate contrasts between groups for continuous outcomes. The fixed factors were group, diagnosis, biologics failure history, centre, time-point, and the interaction (group x time).
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.15

    Secondary: ∆Pain VAS

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    End point title
    		 ∆Pain VAS
    End point description
    Change in pain VAS from baseline to month 18.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    5.6 ( 3.2 )
    1.0 ( 3.5 )
    Statistical analysis title
    		 SAP pain VAS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the CONSORT statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Repeated measures, linear mixed-effects models were applied to evaluate contrasts between groups for continuous outcomes. The fixed factors were group, diagnosis, biologics failure history, centre, time-point, and the interaction (group x time).
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 9.3

    Secondary: ∆Fatigue VAS

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    End point title
    		 ∆Fatigue VAS
    End point description
    Change in patient fatigue VAS between baseline and 18 months
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    -1.2 ( 4.4 )
    -2.7 ( 4.7 )
    Statistical analysis title
    		 SAP fatigue VAS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the CONSORT statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Repeated measures, linear mixed-effects models were applied to evaluate contrasts between groups for continuous outcomes. The fixed factors were group, diagnosis, biologics failure history, centre, time-point, and the interaction (group x time).
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 7.4

    Secondary: ∆Patient global health VAS

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    End point title
    		 ∆Patient global health VAS
    End point description
    Change in patient global health VAS between baseline and 18 months
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    2.8 ( 3.9 )
    0.9 ( 4.2 )
    Statistical analysis title
    		 SAP patient global helath VAS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 7.2

    Secondary: ∆SF-36 PCS

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    End point title
    		 ∆SF-36 PCS
    End point description
    Change in SF-36 PCS from baseline to 18 months
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    -2.1 ( 1.4 )
    -2.5 ( 1.5 )
    Statistical analysis title
    		 SAP SF-36 PCS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The Control group v The tapering group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 2.4

    Secondary: ∆SF-36 MCS

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    End point title
    		 ∆SF-36 MCS
    End point description
    Change in SF-36 MCS from baseline to month 18
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    -1.6 ( 1.8 )
    -1.5 ( 1.9 )
    Statistical analysis title
    		 SAP SF-36 MCS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The Control group v The tapering group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 2.4

    Secondary: ∆Physician global helath VAS

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    End point title
    		 ∆Physician global helath VAS
    End point description
    Change in Physician global health VAS from baseline to month 18.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    4.9 ( 2.1 )
    4.1 ( 2.3 )
    Statistical analysis title
    		 SAP physician global health VAS
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 3.9

    Secondary: ∆Tender joint count

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    End point title
    		 ∆Tender joint count
    End point description
    Change in tender joint counts between baseline and month 18
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 1
        least squares mean (standard error)
    -0.05 ( 0.4 )
    0.6 ( 0.5 )
    Statistical analysis title
    		 SAP tender joint count
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0

    Secondary: ∆Swollen joint count

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    End point title
    		 ∆Swollen joint count
    End point description
    Change in swollen joint count between baseline and 18 months.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 1
        least squares mean (standard error)
    0.3 ( 0.2 )
    0.3 ( 0.2 )
    Statistical analysis title
    		 SAP swollen joints counts
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.3

    Secondary: ∆CRP

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    End point title
    		 ∆CRP
    End point description
    Change in CRP between baseline and month 18.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 The tapering group The Control group
    Number of subjects analysed
    95
    47
    Units: 0.1
        least squares mean (standard error)
    3.2 ( 1.5 )
    0.7 ( 1.6 )
    Statistical analysis title
    		 SAP CRP
    Statistical analysis description
    Analyses were performed and reported in accordance with the prespecified statistical analysis plan and the Consolidated Standards of Reporting Trials (CONSORT) statements. The primary analyses were based on intention to treat, i.e. all randomized patients, independent of protocol deviations. Categorical outcomes were analysed using generalized linear models for binomial data; missing data were handled as trial failures i.e., not achieving a 50% or greater reduction of the biological dose.
    Comparison groups
    The tapering group v The Control group
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 4.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to month 18.
    Adverse event reporting additional description
    Safety outcomes: serious adverse events, serious infections, non-serious infections, cardiovascular events, malignancy, death, uveitis flare, skin or nail psoriasis flare, IBD flare, biologic discontinuation due to any adverse event, arthritis flare, and persistant (≥12 weeks) arthritis flare.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Tapering group
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 Tapering group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 47 (10.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignancy
    Additional description: Malignancy during the study period (from baseline to month 18).
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Other serious adverse events
    Additional description: Other serious adverse events during the study period (from baseline to month 18).
         subjects affected / exposed
    3 / 95 (3.16%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular events
    Additional description: Cardiovascular events through the study period (from baseline to month 18).
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Serious infections
    Additional description: Serious infections during the study period (baseline to 18 months)
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tapering group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 95 (81.05%)
    25 / 47 (53.19%)
    Investigations
    Discontinued bDMARD due to any AE
    Additional description: Discontinued bDMARD due to any adverse event during the study period (from baseline to month 18).
         subjects affected / exposed
    5 / 95 (5.26%)
    4 / 47 (8.51%)
         occurrences all number
    5
    6
    Fulfil arthritis flare criteria
    Additional description: Fulfil the pre-specified arthritis flare criteria during the study period (from baseline to month 18).
         subjects affected / exposed
    39 / 95 (41.05%)
    10 / 47 (21.28%)
         occurrences all number
    50
    16
    Symptoms of arthritis flare
    Additional description: Symptoms of arthritis flare but does not fulfil the arthritis flare criteria during the study period (from baseline to month 18).
         subjects affected / exposed
    38 / 95 (40.00%)
    6 / 47 (12.77%)
         occurrences all number
    78
    11
    Eye disorders
    Uveitis flare
    Additional description: Uveitis flare during the study period (from baseline to month 18).
         subjects affected / exposed
    5 / 95 (5.26%)
    3 / 47 (6.38%)
         occurrences all number
    7
    4
    Gastrointestinal disorders
    IBD flare
    Additional description: Inflammatory bowel disease flare during the study period (from baseline to month 18).
         subjects affected / exposed
    3 / 95 (3.16%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    Psoriasis skin flare
    Additional description: Psoriasis skin flare during the study period (from baseline to month 18).
         subjects affected / exposed
    4 / 95 (4.21%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    Psoriasis nail flare
    Additional description: Psoriasis nail flare during the study period (from baseline to month 18).
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Non-serious infections
    Additional description: Non-serious infections during the study period (from baseline to month 18).
         subjects affected / exposed
    52 / 95 (54.74%)
    24 / 47 (51.06%)
         occurrences all number
    103
    49

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2019
    The eligibility criteria was revised to allow inclusion of patients in sustained low disease activity (LDA) in stead of just sustained remission.
    20 Mar 2020
    Due to the national implication of the COVID-19 pandemic to the Danish health care system, remote monitoring by telephone contact was allowed for the following visits: month 4, month 8, month 12, and month 24. The primary endpoint assessment (visit 18 month) was considered to be essential to the patients and the trial; therefore, the visit was conducted as an outpatient consultation in order with the protocol. Similarly, subacute visits due to symptoms of flare were considered to be essential; thus, encouraged to be conducted as an outpatient consultation.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Suspension of patient enrolment due to the national implication of the COVID-19 pandemic to the Danish health care system.
    20 Mar 2020
    02 Apr 2020
    The inclusion period was closed 1 month before scheduled due to the continued national COVID-19 implication to the Danish health care system
    02 Apr 2020
    12 Jun 2020
    Remote monitoring, due to the implication of the COVID-19 pandemic, was lifted; thus, all trial visits were onwards conducted as an outpatient consultation in accordance with the trial protocol.
    12 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In total, 142 patients out of the planned 180 patients was enrolled before the inclusion period was closed pre-maturely due to the national implications of the COVID-19 pandemic on the Danish health care system.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31292181
    http://www.ncbi.nlm.nih.gov/pubmed/36745114
    http://www.ncbi.nlm.nih.gov/pubmed/37271939
    http://www.ncbi.nlm.nih.gov/pubmed/39043980
    For support, Contact us.
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