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    Clinical Trial Results:
    REDO study: RhEumatoid arthritis REtreatment with ultra-low dose Rituximab: Disease Outcome after Dose Optimization

    Summary
    EudraCT number
    		 2016-002908-15
    Trial protocol
    		 NL  
    Global end of trial date
    25 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2021
    First version publication date
    07 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RR-152-REDO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch trial register: NL5936
    Sponsors
    Sponsor organisation name
    Sint Maartenskliniek
    Sponsor organisation address
    Hengstdal 3, Ubbergen, Netherlands, 6574 NA
    Public contact
    Lise Verhoef, Sint Maartenskliniek, L.Verhoef@maartenskliniek.nl
    Scientific contact
    Lise Verhoef, Sint Maartenskliniek, L.Verhoef@maartenskliniek.nl
    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
    15 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the difference in efficacy between two ultra-low doses (1 x 200 mg and 1 x 500 mg) and standard low dose (1 x 1000 mg) of rituximab retreatment on the change in DAS28-CRP, compared to a pre-specified non-inferiority margin of 0.6, at 3 and 6 months in patients with RA previously treated with RTX using a conventional dose
    Protection of trial subjects
    Patients were monitored closely during follow-up. In case of disease flare, an extra dose of 1 x 1000 mg RTX could be given without unblinding since the registered dose of RTX is 2 x 1000 mg per 6 months and patients will never exceed this dose (maximum study dose is 1 x 1000 mg).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 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)
    63
    From 65 to 84 years
    78
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from 15 December 2016 until 20 September 2018

    Pre-assignment
    Screening details
    		 679 individuals with rheumatoid arthritis who were using rituximab were screened for inclusion in the study. 340 (50%) people did not meet criteria for inclusion, mainly because of an insufficient response after the last rituximab infusion. A further 196 (29%) individuals did not want to participate. 143 patients were randomised (1 excluded).

    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, Monitor, Carer, Assessor
    Blinding implementation details
    Patients and all people involved in treatment of patients and assessment of outcomes (researchers and care providers) were unaware of the random assignments during the study period. The physical appearance of the three interventions was identical (same volume and colour). Allocation was revealed to every patient (and relevant study staff) by the treating rheumatologist after the last study measurement (at 6 months).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1x1000mg rituximab (control)
    Arm description
    		 Patients received 1x1000mg (standard low dose) rituximab at study start.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rixathon
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 x 1000mg rituximab

    Arm title
    		 1x500mg rituximab
    Arm description
    		 Patients received 1x500mg rituximab at study start
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rixathon
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 x 500mg rituximab

    Arm title
    		 1x200mg rituximab
    Arm description
    		 Patients received 1x200mg rituximab at study start.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rixathon
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 x 200mg rituximab

    Number of subjects in period 1
    		1x1000mg rituximab (control) 1x500mg rituximab 1x200mg rituximab
    Started
    29
    58
    55
    Completed
    29
    58
    54
    Not completed
    0
    0
    1
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1x1000mg rituximab (control)
    Reporting group description
    		 Patients received 1x1000mg (standard low dose) rituximab at study start.

    Reporting group title
    1x500mg rituximab
    Reporting group description
    		 Patients received 1x500mg rituximab at study start

    Reporting group title
    1x200mg rituximab
    Reporting group description
    		 Patients received 1x200mg rituximab at study start.

    Reporting group values
    		 1x1000mg rituximab (control) 1x500mg rituximab 1x200mg rituximab Total
    Number of subjects
    		 29 58 55 142
    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
    Age at baseline
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ± 9.0 64.0 ± 10.9 64.2 ± 12.2 -
    Gender categorical
    Gender of participants
    Units: Subjects
        Female
    		 18 37 40 95
        Male
    		 11 21 15 47

    End points

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    End points reporting groups
    Reporting group title
    1x1000mg rituximab (control)
    Reporting group description
    		 Patients received 1x1000mg (standard low dose) rituximab at study start.

    Reporting group title
    1x500mg rituximab
    Reporting group description
    		 Patients received 1x500mg rituximab at study start

    Reporting group title
    1x200mg rituximab
    Reporting group description
    		 Patients received 1x200mg rituximab at study start.

    Subject analysis set title
    1x1000mg (control) per-protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    For the per-protocol analysis, we included patients who had received study medication and completed followup of 6 months, or until treatment failure (with disease activity LOCF).

    Subject analysis set title
    1x500mg per-protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    For the per-protocol analysis, we included patients who had received study medication and completed followup of 6 months, or until treatment failure (with disease activity LOCF).

    Subject analysis set title
    1x200mg per-protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    For the per-protocol analysis, we included patients who had received study medication and completed followup of 6 months, or until treatment failure (with disease activity LOCF).

    Primary: Change in DAS28-CRP from baseline to 6 months

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    End point title
    		 Change in DAS28-CRP from baseline to 6 months
    End point description
    End point type
    Primary
    End point timeframe
    6 months follow-up
    End point values
    		 1x1000mg (control) per-protocol set 1x500mg per-protocol set 1x200mg per-protocol set
    Number of subjects analysed
    28
    58
    54
    Units: DAS28-CRP
        arithmetic mean (confidence interval 95%)
    -0.35 (-0.67 to -0.04)
    0.05 (-0.21 to 0.31)
    -0.38 (-0.68 to -0.09)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The primary analysis was a per-protocol hierarchical testing procedure comparing ultra-low doses with a standard low dose (500 mg vs 1000 mg at 3 months, followed by 500 mg vs 1000 mg at 6 months, 200 mg vs 1000 mg at 3 months, and 200 mg vs 1000 mg at 6 months), using a non-inferiority margin of 0·60 on change from baseline in the 28-joint disease activity score based on C-reactive protein levels (DAS28-CRP).
    Comparison groups
    1x1000mg (control) per-protocol set v 1x500mg per-protocol set v 1x200mg per-protocol set
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    6 months follow-up
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Complete trial
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: As this was a trial in which dose reduction of rituximab was investigated, very low risk of adverse events due to study interventions was present and we will not specifiy all non-serious adverse events that occurred durint the trial.
    Serious adverse events
    		 Complete trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 140 (9.29%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Acute type-B dissection
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Inguinal hernia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Elective surgery foot
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract extraction
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spondylodiscitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pleural infection
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Complete trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 140 (0.00%)

    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.
    None reported
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