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    Clinical Trial Results:
    A randomized, doubleblind, placebo-controlled multicenter trial to evaluate the safety and efficacy of rituximab (Mabthera) in subjects with new onset myasthenia gravis; the RINOMAX study

    Summary
    EudraCT number
    		 2015-005749-30
    Trial protocol
    		 SE  
    Global end of trial date
    22 Nov 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    2015-00887
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02950155
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Neuroimmunology Unit CMM L8;4 Visionsgatan 18, Stockholm, Sweden, 17176
    Public contact
    Fredrik Piehl, Karolinska Institutet, +46 736718101, fredrik.piehl@ki.se
    Scientific contact
    Fredrik Piehl, Karolinska Institutet, +46 736718101, fredrik.piehl@ki.se
    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
    10 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if rituximab is more effective than placebo to achieve minimal disease manifestations defined as a QMG score ≤ 4 and a daily dose of prednisolone of ≤ 10 mg/d at week 16, with no need of rescue treatment procedure(s) during study weeks 9 to 16.
    Protection of trial subjects
    Worsening in MG symptoms would first be addressed by optimising the acetylcholine esterase inhibitor dose, but if not enough, by raising corticosteroids or starting rescue-treatment
    Background therapy
    		 Acetylcholine esterase inhibitors without limits. Intravenous immunoglobulins and/or plasma exchange allowed during run-in phase. Prednisolone ≤ 40 mg/day also allowed, but tapered to ≤ 10 mg/day during run-in phase.
    Evidence for comparator
    		 The objective of the study was to address any possible benefit of rituximab added to standard of care, which justified the use of placebo as a comparator
    Actual start date of recruitment
    20 Oct 2016
    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
    Sweden: 47
    Worldwide total number of subjects
    47
    EEA total number of subjects
    47
    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)
    17
    From 65 to 84 years
    29
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Specialized care with recruitment from 7 Swedish region based community samples, i.e. regional community-based catchment areas for five Swedish university clinics and two larger regional neurology clinics. Screening occurred between October 20th, 2016, and March 2nd, 2020

    Pre-assignment
    Screening details
    		 87 potentially eligible patients were screened, out of which 47 were enrolled. Reasons for not being included: not fulfilling inclusion criteria, 10; having exclusion criteria, 21; not providing consent, 6; not stated, 4.

    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, Data analyst, Assessor
    Blinding implementation details
    Randomization and preparation of blinded study drug were performed by a central pharmacy, Apoteket Produktion & Laboratorier (APL; Stockholm, Sweden) and shipped to study centers in identical liquid containers to preserve masking. Patients, investigators and all study personnel were blinded throughout the study duration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 intravenous infusion of 500 mg of rituximab disolved in sodiumchloride to 2 mg rituximab/ml
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Mabthera (rituximab)
    Investigational medicinal product code
    L01FA01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    500 mg rituximab dissolved in sodiumchloride to a final concentration of 2 mg/ml

    Investigational medicinal product name
    Sodiumchloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Sodiumchloride 9mg/ml

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodiumchloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Sodiumchloride 9mg/ml, 250 ml

    Number of subjects in period 1
    		Rituximab Placebo
    Started
    25
    22
    Completed
    25
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 intravenous infusion of 500 mg of rituximab disolved in sodiumchloride to 2 mg rituximab/ml

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Rituximab Placebo Total
    Number of subjects
    		 25 22 47
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.4 ( 13.4 ) 58.0 ( 18.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 18 15 33
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.5 ( 3.7 ) 27.6 ( 5.7 ) -
    Subject analysis sets

    Subject analysis set title
    Full data set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that fullfilled inclusion- and exclusion criteraia and consented to participate (n=47), all received study drug and were included in the data set

    Subject analysis sets values
    		 Full data set
    Number of subjects
    47
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.0 ( 16.6 )
    Gender categorical
    Units: Subjects
        Female
    14
        Male
    33
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 intravenous infusion of 500 mg of rituximab disolved in sodiumchloride to 2 mg rituximab/ml

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Full data set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that fullfilled inclusion- and exclusion criteraia and consented to participate (n=47), all received study drug and were included in the data set

    Primary: Minimal disease manifestation at week 16

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    End point title
    		 Minimal disease manifestation at week 16
    End point description
    minimal disease manifestations defined as a QMG score ≤ 4 and a daily dose of prednisolone of ≤ 10 mg/d at week 16
    End point type
    Primary
    End point timeframe
    week 16
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24 [1]
    21 [2]
    Units: subjects
    17
    6
    Notes
    [1] - missing value 1
    [2] - missing value 1
    Statistical analysis title
    		 Primary outcome, minimal disease manifestations
    Statistical analysis description
    Difference in proportions fulfilling criteria for minimal disease manifestations was analyzed on an intention-to-treat basis with Fisher’s exact test and α=0.05
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 5.11

    Secondary: Change in QMG, week 24

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    End point title
    		 Change in QMG, week 24
    End point description
    Subjects receiving rescue treatment was censored at time of treatment QMG, Quantitative Myasthenia Gravis score
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23 [3]
    13 [4]
    Units: change in score points
        arithmetic mean (standard deviation)
    -6.9 ( 5.6 )
    -5.8 ( 4.6 )
    Notes
    [3] - 2 censored
    [4] - 9 censored
    Statistical analysis title
    		 Change in QMG, week 24
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 2.1

    Secondary: Change in MG-ADL, week 16

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    End point title
    		 Change in MG-ADL, week 16
    End point description
    MG-ADL, Myasthenia Gravis Activities of Daily Living score
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23 [5]
    13 [6]
    Units: change in score points
        arithmetic mean (standard deviation)
    -1.7 ( 2.5 )
    -0.5 ( 3.6 )
    Notes
    [5] - 2 censored
    [6] - 9 censored
    Statistical analysis title
    		 Change in MG-ADL, week 16
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 0.8

    Secondary: Change in MG-QoL, week 16

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    End point title
    		 Change in MG-QoL, week 16
    End point description
    MG-QoL, Myasthenia Gravis Quality of Life questionnaire
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22 [7]
    15 [8]
    Units: change in score points
        arithmetic mean (standard deviation)
    -9.2 ( 9.2 )
    -7.0 ( 9.3 )
    Notes
    [7] - 3 censored
    [8] - 7 censored
    Statistical analysis title
    		 Change in MG-QoL, week 16
    Statistical analysis description
    Subjects receiving rescue treatment was censored at time of treatment
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 3.8

    Secondary: Change in QMG, week 24 (post-hoc)

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    End point title
    		 Change in QMG, week 24 (post-hoc)
    End point description
    QMG, Quantitative Myasthenia Gravis score Intention-to-treat analysis for secondary endpoints using worst rank imputation for those receiving rescue therapy
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24 [9]
    21 [10]
    Units: change in score points
        arithmetic mean (standard deviation)
    -6.5 ( 5.9 )
    -2.0 ( 6.0 )
    Notes
    [9] - missing data 1
    [10] - missing data 1
    Statistical analysis title
    		 Change in QMG, week 24
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 -1

    Secondary: Change in MG-ADL, week 16 (post-hoc)

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    End point title
    		 Change in MG-ADL, week 16 (post-hoc)
    End point description
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23 [11]
    21 [12]
    Units: change in score points
        arithmetic mean (standard deviation)
    -1.3 ( 3.2 )
    2.0 ( 5.0 )
    Notes
    [11] - missing data 2
    [12] - missing data 1
    Statistical analysis title
    		 Change in MG-ADL, week 16
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 -0.8

    Secondary: Change in MG-QoL, week 16 (post-hoc)

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    End point title
    		 Change in MG-QoL, week 16 (post-hoc)
    End point description
    MG-QoL, Myasthenia Gravis Quality of Life questionnaire Intention-to-treat analysis for secondary endpoints using worst rank imputation for those receiving rescue therapy
    End point type
    Secondary
    End point timeframe
    week 16
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23 [13]
    21 [14]
    Units: change in score points
        arithmetic mean (standard deviation)
    -8.4 ( 10.2 )
    -2.1 ( 11.1 )
    Notes
    [13] - missing data 2
    [14] - missing data 1
    Statistical analysis title
    		 Change in MG-QoL, week 16
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 -0.1

    Other pre-specified: Minimal disease manifestations week 24

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    End point title
    		 Minimal disease manifestations week 24
    End point description
    Minimal disease manifestation, prednisolone ≤ 10 mg daily and no rescue therapy at week 24
    End point type
    Other pre-specified
    End point timeframe
    week 24
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    21 [15]
    Units: subjects
    18
    8
    Notes
    [15] - missing data 1
    Statistical analysis title
    		 Minimal disease manifestations week 24
    Comparison groups
    Placebo v Rituximab
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 3.44

    Other pre-specified: Rescue treatment before 24 weeks

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    End point title
    		 Rescue treatment before 24 weeks
    End point description
    Rescue treatment given weeks 9-24
    End point type
    Other pre-specified
    End point timeframe
    Weeks 9-24
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    22
    Units: subjects
    1
    8
    Statistical analysis title
    		 Rescue treatment before 24 weeks
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.81

    Other pre-specified: Antibody titers week 24

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    End point title
    		 Antibody titers week 24
    End point description
    serum acetylcholine receptor (AChR+) antibody titers at week 24
    End point type
    Other pre-specified
    End point timeframe
    week 24
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    16 [16]
    19
    Units: nmol/L
        arithmetic mean (standard deviation)
    14.1 ( 21.8 )
    118.8 ( 228.5 )
    Notes
    [16] - 2 subjects AChR negative, several missing data
    Statistical analysis title
    		 Antibody titer
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -104.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -205.3
         upper limit
    		 -4.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From administration of study drug to week 48
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    CT
    Reporting groups
    Reporting group title
    active treatment
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 active treatment placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
    4 / 22 (18.18%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thymoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: In context of myocardial infarction and anoxic myocardial dysfunction with MG respiratory crisis in in the active and placebo treatment arms, respectively
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Subileus
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Vertebral compression fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 active treatment placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 25 (84.00%)
    17 / 22 (77.27%)
    Cardiac disorders
    Arrythmia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Fever of unknown cause
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 22 (9.09%)
         occurrences all number
    3
    2
    Eye disorders
    Conjunctivitis viral
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    5 / 25 (20.00%)
    2 / 22 (9.09%)
         occurrences all number
    5
    2
    Dry mouth
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 22 (9.09%)
         occurrences all number
    3
    2
    Rectal bleeding
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 22 (18.18%)
         occurrences all number
    2
    4
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Renal stone
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Muscle cramps
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    Musculoskeletal pain
         subjects affected / exposed
    10 / 25 (40.00%)
    4 / 22 (18.18%)
         occurrences all number
    10
    4
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    7 / 25 (28.00%)
    10 / 22 (45.45%)
         occurrences all number
    7
    10
    Urinary tract infection bacterial
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2017
    Prolonging the inclusion period to end of q4 2020
    26 Oct 2018
    change of PI at trial site
    26 Apr 2021
    Clarifying open label treatment with rituximab at any time between baseline and 24 weeks as rescue therapy, extending the time window for efficacy evaluation visits from +/- 7 to +/- 21 days and changes in the statistical analysis plan, this comprised changing from using linear regression for analyses of change in secondary outcomes, to the use of Mann-Whitneys U-test for the analysis of differences in change, but still using linear regression to establish 95% CIs.

    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.
    Imbalances in some baseline characteristics, censoring of subjects receiving rescue treatment affected affected per-protocol secondary outcome analyses
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