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    Clinical Trial Results:
    B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis

    Summary
    EudraCT number
    		 2012-000145-12
    Trial protocol
    		 GB  
    Global end of trial date
    12 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2018
    First version publication date
    01 Feb 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    5997
    Additional study identifiers
    ISRCTN number
    		 ISRCTN03978701
    US NCT number
    		 NCT02376335
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC reference: 12/NE/0095
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Level 1 Regent Point, Regent Point Road, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Professor David E Jones, Newcastle University, 44 0191 2087572, david.jones@ncl.ac.uk
    Scientific contact
    Professor David E Jones, Newcastle University, 44 0191 2087572, david.jones@ncl.ac.uk
    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
    14 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of B-cell depleting therapy in Primary Biliary Cirrhosis patients followed up for 12 months. 1. Does Rituximab therapy significantly improve the fatigue experienced by patients with PBC? 2. Does any improvement in fatigue result from a reduction in the PDH-directed antibody response in PBC and the effects that these antibodies have on muscle cell energy generation? 3. What is the safety profile of Rituximab therapy in patients with PBC? 4. How sustained is any effect of Rituximab on fatigue?
    Protection of trial subjects
    No actions required.
    Background therapy
    		 Ursodeoxycholic acid (UDCA) therapy was permitted. Usual dose was 12-15mg/kg body weight which was taken once daily although some patients took it in split dose as long as they took the total of the above calculated dose.
    Evidence for comparator
    		 This was a placebo controlled study.
    Actual start date of recruitment
    01 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    52
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited to the study between 01 October 2012 and 01 October 2015. Participants were identified either through routine clinic outpatient appointments by their treating physician at Newcastle, by their treating physician through Patient Identification Centres (PICs) in the NE region or through the UKPBC platform.

    Pre-assignment
    Screening details
    		 Screening assessments of potential participants took place at the Clinical Research Facility in Newcastle and had to occur within 4 weeks prior to baseline. An eligibility screening form was completed to document participants’ fulfilment of the entry criteria for all patients considered for the study and subsequently included or excluded.

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was a web based system on a 1:1 ratio (rituximab:placebo) using random-permuted blocks with random block length. The treatment arm was kept blinded from the subjects, investigators and study assessors until study completion. The randomisation system generated a treatment arm for each participant that linked to the corresponding allocated study drug (blinded).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 1
    		Rituximab Placebo
    Started
    29
    28
    Completed
    29
    28
    Period 2
    Period 2 title
    Randomisation to first IMP infusion
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    As Period 1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 2
    		Rituximab Placebo
    Started
    29
    28
    Completed
    27
    28
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    1
    -
    Period 3
    Period 3 title
    First IMP infusion to 12 week visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    As Period 1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 3
    		Rituximab Placebo
    Started
    27
    28
    Completed
    27
    28
    Period 4
    Period 4 title
    12 week visit to 6 month visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    As Period 1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 4
    		Rituximab Placebo
    Started
    27
    28
    Completed
    27
    28
    Period 5
    Period 5 title
    6 month visit to 9 month visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    As Period 1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 5
    		Rituximab Placebo
    Started
    27
    28
    Completed
    26
    28
    Not completed
    1
    0
         Lost to follow-up
    1
    -
    Period 6
    Period 6 title
    9 month visit to 12 month visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    As Period 1

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab (1000mg IV) infusion on days 1 and 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg IV on days 1 and 15. First infusion at an initial rate of 50mg/h; after first 30 minutes it could be escalated in 50mg/h increments every 30 minutes, to a maximum of 400mg/h. Second dose could be infused at an initial rate of 100mg/h, and increased by 100mg/h at 30 min intervals to a max of 400mg/h.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Arm type
    		 Placebo

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    250ml IV infusion on days 1 and 15

    Number of subjects in period 6
    		Rituximab Placebo
    Started
    26
    28
    Completed
    24
    26
    Not completed
    2
    2
         Trial terminated early
    2
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15

    Reporting group values
    		 Rituximab Placebo Total
    Number of subjects
    		 29 28 57
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 26 25 51
        From 65-84 years
    		 2 2 4
        Not recorded
    		 1 1 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 55.9 (48.8 to 60.0) 53.3 (49.9 to 58.8) -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 55
        Male
    		 1 1 2
    Ethnicity
    Units: Subjects
        White
    		 27 28 55
        Non-white
    		 1 0 1
        Not recorded
    		 1 0 1
    Smoking history
    Units: Subjects
        Never
    		 16 12 28
        Past
    		 7 8 15
        Current
    		 6 8 14
    Patient location
    Managed by Newcastle CRESTA centre for at least 1 year
    Units: Subjects
        Number of patients managed for at least 1 year
    		 20 19 39
        Number of patients not managed for at least 1 year
    		 9 9 18
    UDCA use
    Whether patients use UDCA
    Units: Subjects
        Use UDCA
    		 24 27 51
        Do not use UDCA
    		 5 1 6
    UDCA Responder
    Patients using UDCA, number who are responders
    Units: Subjects
        UDCA Responder
    		 19 16 35
        UDCA non-responder
    		 5 11 16
        Non UDCA user
    		 5 1 6
    Alcohol consumption
    Alcohol consumption all (including non-drinkers) units per week Units per week - drinkers: Rituximab n=17 (median=4, (IQR=2-8)) Placebo n=9 (median 4, (IQR=2-12)
    Units: Units per week (including non-drinkers)
        median (inter-quartile range (Q1-Q3))
    		 1 (0 to 4) 0 (0 to 1.5) -
    BMI
    Body Mass Index
    Units: Scale
        median (inter-quartile range (Q1-Q3))
    		 28.7 (24.5 to 30.5) 26.7 (22.9 to 30.7) -
    UK PBC risk score at 10 years
    UK PBC risk score at 10 years Number of patients for whom UK PBC risk score at 10 years available: Rituximab: 25 Placebo: 27
    Units: Scale score
        median (inter-quartile range (Q1-Q3))
    		 1.26 (0.94 to 1.74) 1.75 (1.12 to 3.04) -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15

    Primary: Fatigue severity in PBC patients at 3 months

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    End point title
    		 Fatigue severity in PBC patients at 3 months
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks (3 months)
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    36.2 ± 8.4
    38.1 ± 8.7
    Statistical analysis title
    		 Adjusted mean difference of PBC-40 fatigue domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 fatigue domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Fatigue severity in PBC patients at 6 months

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    End point title
    		 Fatigue severity in PBC patients at 6 months
    End point description
    Fatigue severity in PBC patients, assessed using the fatigue domain score of the PBC-40, a fully validated, psychometrically robust, disease specific quality of life measure, evaluated at baseline and 12 weeks, 6, 9 and 12 months (PBC-40 fatigue domain score >33 at outset).
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 fatigue domain data at both baseline and 6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    36.6 ± 7.6
    39.9 ± 7.5
    No statistical analyses for this end point

    Secondary: Fatigue severity in PBC patients at 9 months

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    End point title
    		 Fatigue severity in PBC patients at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 fatigue domain data at both baseline and 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    38.1 ± 8.3
    39.6 ± 8.6
    No statistical analyses for this end point

    Secondary: Fatigue severity in PBC patients at 12 months

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    End point title
    		 Fatigue severity in PBC patients at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 fatigue domain data at both baseline and 12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    39.5 ± 8.2
    39.6 ± 6.5
    No statistical analyses for this end point

    Secondary: Symptom severity score for itch domain of PBC-40 questionnaire at 12 weeks

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    End point title
    		 Symptom severity score for itch domain of PBC-40 questionnaire at 12 weeks
    End point description
    Symptom severity score for itch domain of PBC-40 questionnaire at 12 weeks
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 itch domain data at both baseline and 12 week visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.5 ± 2.8
    5.5 ± 3.5
    Statistical analysis title
    		 Adjusted mean difference of PBC-40 itch domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 itch domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 1.8

    Secondary: Symptom severity score for itch domain of PBC-40 questionnaire at 6 months

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    End point title
    		 Symptom severity score for itch domain of PBC-40 questionnaire at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 itch domain data at both baseline and 6 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.3 ± 2.7
    6.4 ± 3.6
    No statistical analyses for this end point

    Secondary: Symptom severity score for itch domain of PBC-40 questionnaire at 9 months

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    End point title
    		 Symptom severity score for itch domain of PBC-40 questionnaire at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 itch domain data at both baseline and 9 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.4 ± 3.1
    6.4 ± 3.4
    No statistical analyses for this end point

    Secondary: Symptom severity score for itch domain of PBC-40 questionnaire at 12 months

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    End point title
    		 Symptom severity score for itch domain of PBC-40 questionnaire at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 itch domain data at both baseline and 12 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.7 ± 3.8
    6.2 ± 3.0
    No statistical analyses for this end point

    Secondary: Symptom severity score for cognitive domain of PBC-40 questionnaire at 3 months

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    End point title
    		 Symptom severity score for cognitive domain of PBC-40 questionnaire at 3 months
    End point description
    Symptom severity score for cognitive domain of PBC-40 questionnaire.
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 cognitive domain data at both baseline and 3 month visits.
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    19.3 ± 4.0
    18.3 ± 5.7
    Statistical analysis title
    		 Adjusted mean difference PBC-40 cognitive domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 cognitive domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 3.3

    Secondary: Symptom severity score for cognitive domain of PBC-40 questionnaire at 9 months

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    End point title
    		 Symptom severity score for cognitive domain of PBC-40 questionnaire at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 cognitive domain data at both baseline and 9 month visits.
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    19.2 ± 4.5
    19.0 ± 4.8
    No statistical analyses for this end point

    Secondary: Symptom severity score for cognitive domain of PBC-40 questionnaire at 12 months

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    End point title
    		 Symptom severity score for cognitive domain of PBC-40 questionnaire at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 cognitive domain data at both baseline and 12 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    19.6 ± 3.0
    20.0 ± 4.7
    No statistical analyses for this end point

    Secondary: Symptom severity score for social domain of PBC-40 questionnaire at 12 weeks

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    End point title
    		 Symptom severity score for social domain of PBC-40 questionnaire at 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social domain data at both baseline and 12 weeks visit
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    32.6 ± 7.1
    30.8 ± 7.4
    Statistical analysis title
    		 Adjusted mean difference of PBC-40 social domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 social domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 5

    Secondary: Symptom severity score for social domain of PBC-40 questionnaire at 6 months

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    End point title
    		 Symptom severity score for social domain of PBC-40 questionnaire at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social domain data at both baseline and 6 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    31.9 ± 8.3
    32.9 ± 8.1
    No statistical analyses for this end point

    Secondary: Symptom severity score for social domain of PBC-40 questionnaire at 9 months

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    End point title
    		 Symptom severity score for social domain of PBC-40 questionnaire at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social domain data at both baseline and 9 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    32.2 ± 7.6
    31.3 ± 8.1
    No statistical analyses for this end point

    Secondary: Symptom severity score for social domain of PBC-40 questionnaire at 12 months

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    End point title
    		 Symptom severity score for social domain of PBC-40 questionnaire at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social domain data at both baseline and 12 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    32.5 ± 7.6
    30.3 ± 7.5
    No statistical analyses for this end point

    Secondary: Symptom severity score for emotional domain of PBC-40 at 12 weeks

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    End point title
    		 Symptom severity score for emotional domain of PBC-40 at 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social emotional data at both baseline and 12 week visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    9.3 ± 3.3
    9.0 ± 3.2
    Statistical analysis title
    		 Adjusted mean difference PBC-40 emotional domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 emotional domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Placebo v Rituximab
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2

    Secondary: Symptom severity score for emotional domain of PBC-40 at 6 months

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    End point title
    		 Symptom severity score for emotional domain of PBC-40 at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social emotional data at both baseline and 6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    9.3 ± 3.5
    9.6 ± 3.6
    No statistical analyses for this end point

    Secondary: Symptom severity score for emotional domain of PBC-40 at 9 months

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    End point title
    		 Symptom severity score for emotional domain of PBC-40 at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social emotional data at both baseline and 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    9.1 ± 3.5
    9.6 ± 3.4
    No statistical analyses for this end point

    Secondary: Symptom severity score for emotional domain of PBC-40 at 12 months

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    End point title
    		 Symptom severity score for emotional domain of PBC-40 at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 social emotional data at both baseline and 12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22
    25
    Units: Scale Score
        arithmetic mean (standard deviation)
    9.0 ± 2.9
    9.1 ± 3.4
    No statistical analyses for this end point

    Secondary: Symptom severity for other symptoms domain of PBC-40 at 12 weeks

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    End point title
    		 Symptom severity for other symptoms domain of PBC-40 at 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 other symptoms domain data at both baseline and 12 week visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    16.9 ± 3.7
    17.6 ± 3.3
    Statistical analysis title
    		 Adjusted mean difference PBC-40 symptoms domain
    Statistical analysis description
    Adjusted mean difference of PBC-40 symptoms domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 1.5

    Secondary: Symptom severity for other symptoms domain of PBC-40 at 6 months

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    End point title
    		 Symptom severity for other symptoms domain of PBC-40 at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 other symptoms domain data at both baseline and 6 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    18.2 ± 4.9
    18.2 ± 3.5
    No statistical analyses for this end point

    Secondary: Symptom severity for other symptoms domain of PBC-40 at 9 months

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    End point title
    		 Symptom severity for other symptoms domain of PBC-40 at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 other symptoms domain data at both baseline and 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    17.8 ± 5.1
    18.1 ± 4.0
    No statistical analyses for this end point

    Secondary: Symptom severity for other symptoms domain of PBC-40 at 12 months

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    End point title
    		 Symptom severity for other symptoms domain of PBC-40 at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with non-missing PBC-40 other symptoms domain data at both baseline and 12 month visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    18.5 ± 4.7
    18.9 ± 4.7
    No statistical analyses for this end point

    Secondary: ESS at 12 weeks

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    End point title
    		 ESS at 12 weeks
    End point description
    Epworth Sleepiness Scale (ESS) score to assess daytime somnolence at baseline, 12 weeks, 6, 9 and 12 months
    End point type
    Secondary
    End point timeframe
    Patients with non missing data at both baseline and 12 week visits
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    26
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    10.9 ± 6.1
    11.9 ± 5.1
    Statistical analysis title
    		 Adjusted mean difference of ESS domain
    Statistical analysis description
    Adjusted mean difference of ESS domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1.6

    Secondary: ESS at 6 months

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    End point title
    		 ESS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    ESS score at 6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    27
    Units: Scale Score
        arithmetic mean (standard deviation)
    11.4 ± 5.5
    12.6 ± 5.9
    No statistical analyses for this end point

    Secondary: ESS at 9 months

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    End point title
    		 ESS at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    ESS score at 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    10.8 ± 5.9
    13.3 ± 5.2
    No statistical analyses for this end point

    Secondary: ESS at 12 months

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    End point title
    		 ESS at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    ESS score at 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    11.2 ± 5.8
    11.8 ± 4.5
    No statistical analyses for this end point

    Secondary: OGS at 12 weeks

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    End point title
    		 OGS at 12 weeks
    End point description
    Orthostatic Grading Scale (OGS) score to assess vasomotor autonomic symptoms at baseline, 12 weeks, 6, 9 and 12 months
    End point type
    Secondary
    End point timeframe
    OGS score at 12 weeks
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    26
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.7 ± 4.0
    4.8 ± 4.1
    Statistical analysis title
    		 Adjusted mean difference of OGS domain
    Statistical analysis description
    Adjusted mean difference of OGS domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.9

    Secondary: OGS at 6 months

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    End point title
    		 OGS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    OGS score at 6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    5.5 ± 4.1
    5.7 ± 4.3
    No statistical analyses for this end point

    Secondary: OGS at 9 months

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    End point title
    		 OGS at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    OGS score at 9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    5.7 ± 4.0
    5.4 ± 3.8
    No statistical analyses for this end point

    Secondary: OGS at 12 months

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    End point title
    		 OGS at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    OGS score at 12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    23
    25
    Units: Scale Score
        arithmetic mean (standard deviation)
    4.7 ± 4.1
    5.8 ± 4.1
    No statistical analyses for this end point

    Secondary: PROMIS-HAQ at 6 months

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    End point title
    		 PROMIS-HAQ at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    27
    Units: Scale Score
        arithmetic mean (standard deviation)
    11.2 ± 11.2
    16.5 ± 14.5
    No statistical analyses for this end point

    Secondary: PROMIS-HAQ at 9 months

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    End point title
    		 PROMIS-HAQ at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    12.4 ± 10.5
    17.0 ± 17.1
    No statistical analyses for this end point

    Secondary: PROMIS-HAQ at 12 months

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    End point title
    		 PROMIS-HAQ at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    26
    Units: Sclae Score
        arithmetic mean (standard deviation)
    12.6 ± 11.1
    16.5 ± 15.2
    No statistical analyses for this end point

    Secondary: COGFAIL at 12 weeks

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    End point title
    		 COGFAIL at 12 weeks
    End point description
    Cognitive Failure questionnaire score at baseline, 12 weeks, 6, 9 and 12 months
    End point type
    Secondary
    End point timeframe
    COGFAIL Score at 12 weeks
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    59.7 ± 14.7
    52.9 ± 17.2
    Statistical analysis title
    		 Adjusted mean difference of COGFAIL domain
    Statistical analysis description
    Adjusted mean difference of COGFAIL domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 8.6

    Secondary: COGFAIL at 6 months

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    End point title
    		 COGFAIL at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    27
    26
    Units: Sclae Score
        arithmetic mean (standard deviation)
    57.6 ± 15.7
    54.2 ± 19.2
    No statistical analyses for this end point

    Secondary: COGFAIL at 9 months

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    End point title
    		 COGFAIL at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    57.1 ± 16.2
    54.4 ± 20.1
    No statistical analyses for this end point

    Secondary: COGFAIL at 12 months

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    End point title
    		 COGFAIL at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    57.8 ± 14.7
    55.7 ± 17.3
    No statistical analyses for this end point

    Secondary: HADS at 12 weeks

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    End point title
    		 HADS at 12 weeks
    End point description
    Hospital Anxiety and Depression Scale (HADS) score to assess depressive and anxiety-related symptoms at baseline, 12 weeks, 6, 9 and 12 months
    End point type
    Secondary
    End point timeframe
    HADS score at 12 weeks
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    22
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    12.4 ± 6.5
    12.3 ± 6.7
    Statistical analysis title
    		 Adjusted mean difference of HADS domain
    Statistical analysis description
    Adjusted mean difference of HADS domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 1.2

    Secondary: HADS at 6 months

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    End point title
    		 HADS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    25
    25
    Units: Scale Score
        arithmetic mean (standard deviation)
    13.8 ± 7.9
    14.0 ± 7.9
    No statistical analyses for this end point

    Secondary: HADS at 9 months

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    End point title
    		 HADS at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    26
    Units: Scale Score
        arithmetic mean (standard deviation)
    13.7 ± 8.6
    14.2 ± 7.5
    No statistical analyses for this end point

    Secondary: HADS at 12 months

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    End point title
    		 HADS at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    24
    25
    Units: Scale Score
        arithmetic mean (standard deviation)
    13.0 ± 6.6
    13.0 ± 7.6
    No statistical analyses for this end point

    Secondary: Average perceived fatigue score at 12 weeks

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    End point title
    		 Average perceived fatigue score at 12 weeks
    End point description
    Average perceived fatigue score calculated from participant held diaries at baseline, 12 weeks, 6, 9 and 12 months. The diaries measure fatigue using a scale of 1 to 6, where 1 represents no fatigue and 6 represents extreme fatigue.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    18
    20
    Units: Scale Score
        arithmetic mean (standard deviation)
    3.51 ± 1.04
    3.59 ± 1.11
    Statistical analysis title
    		 Adjusted mean difference of fatigue diary score
    Statistical analysis description
    Adjusted mean difference of fatigue diary score at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.7

    Secondary: Average perceived fatigue score at 6 months

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    End point title
    		 Average perceived fatigue score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    17
    20
    Units: Scale Score
        arithmetic mean (standard deviation)
    3.34 ± 1.07
    3.79 ± 1.10
    No statistical analyses for this end point

    Secondary: Average perceived fatigue score at 9 months

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    End point title
    		 Average perceived fatigue score at 9 months
    End point description
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    18
    20
    Units: Scale Score
        arithmetic mean (standard deviation)
    3.48 ± 1.15
    3.61 ± 1.07
    No statistical analyses for this end point

    Secondary: Average perceived fatigue score at 12 months

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    End point title
    		 Average perceived fatigue score at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    16
    18
    Units: Scale Score
        arithmetic mean (standard deviation)
    3.8 ± 1.09
    3.77 ± 0.97
    No statistical analyses for this end point

    Other pre-specified: PROMIS-HAQ at 12 weeks

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    End point title
    		 PROMIS-HAQ at 12 weeks
    End point description
    Patient-Reported Outcomes Measurement Information System Health Assessment Questionnaire (PROMIS-HAQ) to assess functional status at baseline, 12 weeks, 6, 9 and 12 months
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 Rituximab Placebo
    Number of subjects analysed
    26
    28
    Units: Scale Score
        arithmetic mean (standard deviation)
    13.7 ± 14.0
    14.0 ± 13.1
    Statistical analysis title
    		 Adjusted mean difference of PROMIS-HAQ
    Statistical analysis description
    Adjusted mean difference of PROMIS-HAQ domain at 3 months between Rituximab and placebo arms
    Comparison groups
    Rituximab v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 7.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All non serious adverse events were reported from visit 2 until visit 19 (final study visit at 12 months). Serious Adverse Events (SAEs) were reported throughout the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab (1000mg IV) infusion on days 1 and 15

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride 250ml.) infusion on days 1 and 15

    Serious adverse events
    		 Rituximab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Abdominal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Neuritis
    Additional description: Right optic neuritis followed by left optic neuritis.
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         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: 0%
    Non-serious adverse events
    		 Rituximab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 29 (93.10%)
    28 / 28 (100.00%)
    Surgical and medical procedures
    Coronary angiogram
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Carpal tunnel operation left hand
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Adverse reaction to flu jab (bilateral swelling arms)
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Vacant memory
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 28 (14.29%)
         occurrences all number
    5
    4
    Extreme fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    4
    2
    Restless feeling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Itching of head and throat
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Erythema at cannula site
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Facial flushing
         subjects affected / exposed
    7 / 29 (24.14%)
    3 / 28 (10.71%)
         occurrences all number
    7
    4
    Hot flushes
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    Facial rash
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Facial spots
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Hiatus hernia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Tremulous
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Severe hot flushes
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    shivering
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Shaking to body
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Feeling sluggish
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Systemic itch
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blocked nose
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Running nose
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Sore throat
         subjects affected / exposed
    5 / 29 (17.24%)
    7 / 28 (25.00%)
         occurrences all number
    6
    7
    Cold/sore throat
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Flu like symptoms
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    Cough and cold
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Common cold
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 28 (3.57%)
         occurrences all number
    5
    1
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 28 (14.29%)
         occurrences all number
    1
    4
    Dry cough
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Chesty cough
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Chest tightness with wheeze
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Coryzal symptoms
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Nose bleed
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Increased effort to breathe
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Low mood
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Depression
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Bruising and lacerations to right calf
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Syncopal disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Paroxysmal atrial fibrillation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Lightheaded
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Vasovagal syncope
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Heavy feeling/dull ache to chest
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 29 (44.83%)
    10 / 28 (35.71%)
         occurrences all number
    22
    14
    Migraine
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Swollen ankles
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Numb hands
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Low HB
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Haemangioma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Right sore ear
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 28 (17.86%)
         occurrences all number
    2
    7
    Sinusitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Vertigo
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Ringing in ears
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Eye disorders
    Calcium deposits to right eye
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Diabetic Macularaedema Right Eye
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Glaucoma
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Right Eye Infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Tired eyes
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Bleed in left eye
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal bloating
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Abdominal cramps
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Vomited
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Mild abdominal pains
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Rectal bleeding
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Colic pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Acid reflux
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    7 / 29 (24.14%)
    2 / 28 (7.14%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    6 / 29 (20.69%)
    6 / 28 (21.43%)
         occurrences all number
    7
    8
    Nausea and vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Nausea and diarrhoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tiredness
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Loss of appetite
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Lower abdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Loose stool
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Indigestion
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Stomach pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Stomach ache
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Right upper quadrant pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Sensitivity of skin
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Worsening skin irritation to hands and arms
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Lichen planus
    Additional description: Mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Reaction to local anaesthetic
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    Eczema
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Patches dry/flaky skin
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Itch
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 28 (10.71%)
         occurrences all number
    1
    3
    Itchy legs
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Itchy on left hand
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Cold sore
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
         occurrences all number
    2
    3
    Rash
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Tingling in right arm and jaw
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    4 small cyst-type growths on upper and lower lids, left eye
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Skin erythema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Redness/Itchiness to stomach
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hyperthyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    UTI
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 28 (0.00%)
         occurrences all number
    5
    0
    Frequency urine
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Query scaphoid bone fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Bruising left knee
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Aches and pains
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Aching muscles
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Arthritic pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Backache
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Restless leg
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Bruised ribs secondary to fall
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Swelling to right clavicle
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Muscle ache
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Painful ribs
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    Pain to both breasts
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Painful left knee
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Painful right knee
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Right sided muscular pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Painful legs
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Leg cramp
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Left Tennis Elbow
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Plantar fibromatosis, right foot
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Right sided swelling below clavicle
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Right sided shoulder pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Lower back pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Neck and back pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Fracture Right Radial
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Painful left ankle
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pain knuckles
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pain and burning feeling to muscles
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Right ankle sprain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pulled muscle (intercostals, right side)
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Right foot tenderness
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Right shoulder tenderness
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Joint aches
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Joint pains
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Cramp in hands
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Broken wrist
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Whiplash
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Infections and infestations
    Mouth ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Thrush (vaginal)
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Infection to right calf
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Swollen neck glands
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Swollen throat glands
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Swollen glands and sore throat
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Itch to insect bite left leg
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gum infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tooth pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Flu virus
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Chest infection
         subjects affected / exposed
    0 / 29 (0.00%)
    7 / 28 (25.00%)
         occurrences all number
    0
    7
    Viral illness
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Shingles
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Low iron
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2013
    Addition of Expression of Interest Form, inclusion of Patient Identification Centres, change to Clinical Research Facility Rituximab Infusion Guidelines (protocol appendix 5) and amended Fatigue Diary (protocol appendix 4).
    10 Dec 2013
    Addition of random lipid profile blood tests, addition of Urea and Electrolyte blood tests and clarification of placebo in protocol. Change to SmPC in appendix 1 (dated 04/12/2013).
    10 Dec 2014
    Change to inclusion criteria for women - contraception should be continued for 12 months in line with updated SmPC rather than 3 months. SmPC updated in appendix 1 (dated 06/06/2014). Clarification regarding Hepatitis B, HBV serology and Hepatitis B serology.
    21 Sep 2015
    6-month extension, amended study population and power, addition of UKPBC platform and additional administrative changes to protocol, PIS and ICF.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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