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    Clinical Trial Results:
    RITUXILUP - An open label randomised multicentre controlled trial of RITUXImab and mycophenolate mofetil (MMF) without oral steroids for the treatment of LUPus nephritis

    Summary
    EudraCT number
    2012-004893-25
    Trial protocol
    GB  
    Global end of trial date
    13 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2019
    First version publication date
    02 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO2035
    Additional study identifiers
    ISRCTN number
    ISRCTN84054592
    US NCT number
    NCT01773616
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Imperial College London; Joint Research Compliance Office
    Sponsor organisation address
    Room 221, Medical School Building, St Mary’s Campus, Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Professor Liz Lightstone, Imperial College London, l.lightstone@imperial.ac.uk
    Scientific contact
    Professor Liz Lightstone, Imperial College London, l.lightstone@imperial.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
    17 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The trial aimed to demonstrate that a regimen free of oral steroids but with rituximab and MMF is non-inferior to a regimen based on oral steroids and MMF in achieving the primary outcome of complete renal response at one year.
    Protection of trial subjects
    Data Monitoring Committee Pharmacovigilance On-site and remote monitoring including source data verification Detailed informed consent process
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 May 2014
    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: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    1
    Adults (18-64 years)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Potential patients were identified in clinics and screened against the inclusion and exclusion criteria for the study. Recruitment took place across 11 sites in the UK from May 2015 to April 2017. Recruitment to the trial was halted prematurely in April 2017 at N=25, following withdrawal of funding due to slower than anticipated recruitment.

    Pre-assignment
    Screening details
    Patients were screened for eligibility according to the trial inclusion and exclusion criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable - this is an open label trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Control
    Arm description
    Control arm / Standard of care: 1. Mycophenolate mofetil 2. Methyl prednisolone 3. Oral prednisolone
    Arm type
    Active comparator

    Investigational medicinal product name
    Mycophenolate Mofetil (MMF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing in adults: start MMF 500mg bd and increase weekly by 250mg bd to a maximum dose of 1g bd if 60kg or less and 1.5g bd if >60kg. Within these guidelines the maximum dose will be titrated against white blood cells, tolerability or trough mycophenolic acid levels where available but should be no less than 500mg bd. At 6 months, if patients have responded, as defined by stabilisation of serum creatinine, and proteinuria non nephrotic and >50% reduction from baseline, the maximum dose of MMF will be reduced to 1g bd in those on higher dose initially. Dosing in children aged 12-18: Commence MMF dosing at 600mg/m2 for 3 days up to a maximum of 1g and then increased to 600mg/m2 bd.

    Investigational medicinal product name
    Oral prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral prednisolone commencing at 0.5mg/kg/day (max 60mg/day, minimum 20mg/day) tapered thus: o From week 2: if commencing on >45mg/day, decreased by 10mg/day every 2 weeks to 40mg/day followed by decrease by 5mg/day every 2 weeks until down to 20mg/day if clinical status permits. o From week 2: if commencing on 45mg/day or less, decreased by 5mg/day every 2 weeks until down to 20mg/day if clinical status permits. o However, the dose should be no more than 20mg/day at 12 -13 weeks. o Once down to a dose of 20mg/day, this should be maintained for 4 weeks. o Thereafter, reduced by 2.5mg/day every week down to 10mg/day if clinical status permits. o However, the dose should be no more than 10mg/day once daily by 26 weeks at the latest o Once down to a dose of 10mg/day, this should be maintained for a minimum of 6 weeks. o Thereafter, the steroid dose can be tapered according to clinical status and at a rate determined by clinician.

    Investigational medicinal product name
    Methyl prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500mg Methyl prednisolone IV at Infusion 1/Visit 1 and Infusion 2/Visit 3. If patients have received methyl prednisolone within the 4 weeks prior to randomisation, the dose will be modified to ensure maximum methyl prednisolone given will not exceed 3g in total.

    Arm title
    Rituximab
    Arm description
    Intervention arm: 1. Rituximab 2. Mycophenolate mofetil 3. Methyl prednisolone
    Arm type
    Experimental

    Investigational medicinal product name
    Mycophenolate Mofetil (MMF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing in adults: start MMF 500mg bd and increase weekly by 250mg bd to a maximum dose of 1g bd if 60kg or less and 1.5g bd if >60kg. Within these guidelines the maximum dose will be titrated against white blood cells, tolerability or trough mycophenolic acid levels where available but should be no less than 500mg bd. At 6 months, if patients have responded, as defined by stabilisation of serum creatinine, and proteinuria non nephrotic and >50% reduction from baseline, the maximum dose of MMF will be reduced to 1g bd in those on higher dose initially. Dosing in children aged 12-18: Commence MMF dosing at 600mg/m2 for 3 days up to a maximum of 1g and then increased to 600mg/m2 bd.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 1g infusion at Infusion 1/Visit 1 and Infusion 2/Visit 3 (The dose in children will be 750mg/m2 (maximum 1g) at Infusion 1/Visit 1 and Infusion 2/Visit 3 ). Concomitant IV or oral antihistamines and IV or oral paracetamol will be administered prior to administration of Rituximab.

    Investigational medicinal product name
    Methyl prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500mg Methyl prednisolone IV at Infusion 1/Visit 1 and Infusion 2/Visit 3. If patients have received methyl prednisolone within the 4 weeks prior to randomisation, the dose will be modified to ensure maximum methyl prednisolone given will not exceed 3g in total.

    Number of subjects in period 1
    Control Rituximab
    Started
    12
    13
    Completed
    9
    11
    Not completed
    3
    2
         Lack of efficacy
    -
    1
         Non-compliance with protocol visits
    1
    -
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    Control arm / Standard of care: 1. Mycophenolate mofetil 2. Methyl prednisolone 3. Oral prednisolone

    Reporting group title
    Rituximab
    Reporting group description
    Intervention arm: 1. Rituximab 2. Mycophenolate mofetil 3. Methyl prednisolone

    Reporting group values
    Control Rituximab Total
    Number of subjects
    12 13 25
    Age categorical
    Age in years
    Units: Subjects
        Adolescents (12-17 years)
    0 1 1
        Adults (18-64 years)
    12 12 24
    Age continuous
    Age in years
    Units: years
        median (inter-quartile range (Q1-Q3))
    35.5 (29 to 40.5) 32 (25 to 45) -
    Gender categorical
    Units: Subjects
        Female
    11 11 22
        Male
    1 2 3
    Ethnicity
    Units: Subjects
        Asian
    5 6 11
        Black
    3 2 5
        Mixed
    0 1 1
        White
    4 4 8
    Smoking status
    Units: Subjects
        Never
    8 11 19
        Current Smoker
    1 1 2
        Ex smoker
    3 1 4
    Lupus Nephritis Class
    Units: Subjects
        III or IV + V
    4 11 15
        "pure" class V
    8 2 10
    Height
    Units: cm
        median (inter-quartile range (Q1-Q3))
    162.3 (158 to 170.5) 164 (160.5 to 170) -
    Waist
    Units: cm
        median (inter-quartile range (Q1-Q3))
    76 (70 to 95) 84 (75 to 87) -
    Hip
    Units: cm
        median (inter-quartile range (Q1-Q3))
    94 (86 to 106) 97 (93 to 99) -
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    62.6 (53 to 82.1) 66.7 (54.9 to 76.9) -
    Body Mass Index
    Units: NA
        median (inter-quartile range (Q1-Q3))
    23.4 (20.95 to 28.82) 22.3 (20.02 to 28.94) -
    Temperature
    Units: degrees Celsius
        median (inter-quartile range (Q1-Q3))
    36.5 (36.2 to 36.9) 36.5 (36.2 to 37.1) -
    Heart rate
    Units: bpm
        median (inter-quartile range (Q1-Q3))
    90.5 (72 to 98) 86 (78 to 93) -
    Systolic Blood Pressure - lying
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    123 (118 to 148) 119 (110 to 127) -
    Diastolic Blood Pressure - lying
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    82 (72 to 86) 75.5 (71 to 78) -
    Systolic Blood Pressure - standing
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    129 (116 to 143) 130 (120 to 140) -
    Diastolic Blood Pressure - standing
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    82 (74 to 90) 87 (73 to 89) -

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    Control arm / Standard of care: 1. Mycophenolate mofetil 2. Methyl prednisolone 3. Oral prednisolone

    Reporting group title
    Rituximab
    Reporting group description
    Intervention arm: 1. Rituximab 2. Mycophenolate mofetil 3. Methyl prednisolone

    Primary: Complete renal response (CR) at week 52 (or closest timepoint)

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    End point title
    Complete renal response (CR) at week 52 (or closest timepoint)
    End point description
    CR is defined as: - uPCR ≤50mg/mmol (=<0.5mg/mg) in a spot urine AND - eGFR ≥60ml/min, or if <60ml/min at screening, not fallen by >20% compared to screening/randomisation (whichever worse) AND - In the rituximab arm without the need to prescribe oral steroids within 1 year (beyond the first 8 wks depending on duration of prior steroids), except for 1 course of oral prednisolone max 30mg for a maximum of 14 d OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, each maximum 120mg methylprednisolone or equivalent (in addition to the planned IV methyl prednisolone in the protocol) OR - in the steroid arm without the need for additional steroids over and above the prescribed taper, except for one course of oral prednisolone maximum 30mg for a maximum of 14d OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, maximum 120mg methylprednisolone or equivalent (in addition to planned IV methyl pred)
    End point type
    Primary
    End point timeframe
    Week 52 or closest visit
    End point values
    Control Rituximab
    Number of subjects analysed
    12
    13
    Units: N(%)
        CR
    4
    6
        Non-CR
    8
    7
    Statistical analysis title
    Primary outcome analysis
    Comparison groups
    Control v Rituximab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    3.74

    Secondary: Partial response (PR) at week 52 or closest visit

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    End point title
    Partial response (PR) at week 52 or closest visit
    End point description
    The proportion of patients achieving partial renal response (PR) at week 52 where PR is defined as: - eGFR - no more than a 20% decrease from the baseline value, AND - if not nephrotic at baseline (urine PCR <300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR OR - if nephrotic at baseline (urine PCR >300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR AND urine PCR <300mg/mmol
    End point type
    Secondary
    End point timeframe
    52 weeks or closest visit
    End point values
    Control Rituximab
    Number of subjects analysed
    12
    13
    Units: N(%)
        PR
    9
    11
        Non-PR
    3
    2
    Statistical analysis title
    Secondary outcome analysis
    Comparison groups
    Control v Rituximab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.68

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signing the consent form up to the final study visit.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    Control arm / Standard of care: 1. Mycophenolate mofetil 2. Methyl prednisolone 3. Oral prednisolone

    Reporting group title
    Rituximab
    Reporting group description
    Intervention arm: 1. Rituximab 2. Mycophenolate mofetil 3. Methyl prednisolone

    Serious adverse events
    Control Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 13 (23.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Emotional distress
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Control Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    13 / 13 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Hernia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    8
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Stress fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Loss of libido
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Breast pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    11
    Galactorrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Pleuritic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 13 (23.08%)
         occurrences all number
    3
    5
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 13 (38.46%)
         occurrences all number
    2
    7
    Migraine
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Poor quality sleep
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Eye pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 13 (23.08%)
         occurrences all number
    1
    4
    Noninfective gingivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Alopecia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    6
    Rash maculo-papular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 13 (15.38%)
         occurrences all number
    4
    3
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Joint effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Foot and mouth disease
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hordeolum
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 13 (23.08%)
         occurrences all number
    1
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    Sinusitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 13 (15.38%)
         occurrences all number
    5
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 13 (23.08%)
         occurrences all number
    11
    4
    Vaginal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         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
    18 Apr 2014
    Version 1.1: first approved version - minor changes following Ethics Committee review; clarification about informing patients’ GPs
    06 Mar 2016
    V2.2: clarification regarding MMF recommendations, change of prior steroid use from 4 weeks to 12 weeks (inclusion criteria), increase for allowed methyl prednisolone pre-trial from 1g to 2g (inclusion criteria), clarifications on study assessments including timing of standard care visits, clarifications regarding trial sample handling, inclusion of definition of Adverse Event of Special Interest, clarification for reporting of pregnancy and Adverse Events, clarifications regarding steroid taper (if oral steroids taken before trial entry)
    30 Jun 2017
    V 3.0: administrative changes, amendment to final study visit following decision to terminate trial early – patients to be followed up for a minimum of 6 months and last study visit to be modified to include annual visit procedures, clarification regarding definition of withdrawal.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Sep 2016
    The RITUXILUP study was temporarily on halt as a reassessment of study feasibility was required. The Study Team entered into discussion with the funder (ARUK) regarding how to proceed in order to reach the required recruitment target and to answer the current relevant question. Those who were randomised prior to the halt (n=18) continued to be followed up as per the study protocol.
    11 Oct 2017
    27 Mar 2017
    The RITUXILUP study received an official notification from Arthritis Research UK (the Funder) that their financial support to complete trial recruitment "to target" will be stopped and with the Sponsor's agreement, recruitment to the trial has been suspended. The funder has reviewed the Study's progress in detail and concluded that the target number of patients cannot be recruited within a realistic time period that is considered value for money.
    -

    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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