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    Clinical Trial Results:
    Optimal management of rheumatoid arthritis patients who require biologic therapy (ORBIT study)

    Summary
    EudraCT number
    2009-011268-13
    Trial protocol
    GB  
    Global end of trial date
    05 May 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Apr 2019
    First version publication date
    04 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RN08RH469
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01021735
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    West Glasgow Ambulatory Care Hospital, Dalnair Street, Glasgow, United Kingdom, G3 8SW
    Public contact
    Jurgen Van Melckebeke, NHS Greater Glasgow and Clyde , 0044 141 201 9313, Jurgen.van-melckebeke@ggc.scot.nhs.uk
    Scientific contact
    Duncan Porter, NHS Greater Glasgow and Clyde , 0044 141 452 6176, duncan.porter@ggc.scot.nhs.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
    05 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify whether rituximab therapy or anti-TNF therapy is more effective in improving the clinical symptoms, signs, physical function and health-related quality of life of patients with active rheumatoid arthritis.
    Protection of trial subjects
    As part of the study patients required to attend additional hospital visits and investigations which could be above those considered to be standard care.. The visit schedule and the number and type of investigations were fully explained to patient verbally and in writing via the patient information sheet to ensure patients were fully aware what was entailed in the trial prior to them consenting to the study. The patient information sheet also full explained the design of the study (open label, randomized controlled trial) that half of patient would receive study treatment (Rituximab) with the other half receiving TNF inhibitor therapy. The side effects of TNF Inhibitor therapy were explained in patient information sheets, as where the expected side effects for the investigational medicinal product (Rituximab). All patients were closely monitored throughou the course of the study for adverse events and were advised to report adverse events to their study team as they arose.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Apr 2010
    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: 295
    Worldwide total number of subjects
    295
    EEA total number of subjects
    295
    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)
    228
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study opened to recruitment on 05/04/2010 and closed to recruitment on 18/11/2013. This study was opened to recruitment in the United Kingdom.

    Pre-assignment
    Screening details
    The screening period for the study was up to 28 days prior to randomisation. Prior to screening investigations commencing patient must have provided informed consent to participate in the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Control
    Arm description
    Control - TNF Inhibitor
    Arm type
    Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Experimental
    Arm description
    Experimental (Rituximab)
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion 2 weeks later. Above course can be repeated after a minimum of 20 weeks depending on response – max 3 courses in 12 months

    Number of subjects in period 1
    Control Experimental
    Started
    151
    144
    Completed
    135
    134
    Not completed
    16
    10
         non compliance
    1
    -
         Concomitant illness
    2
    -
         Physician decision
    2
    1
         Adverse event, serious fatal
    1
    1
         illness
    -
    1
         Adverse event, non-fatal
    2
    2
         Consent withdrawn by subject
    4
    4
         Lost to follow-up
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    Control - TNF Inhibitor

    Reporting group title
    Experimental
    Reporting group description
    Experimental (Rituximab)

    Reporting group values
    Control Experimental Total
    Number of subjects
    151 144 295
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    115 113 228
        From 65-84 years
    36 31 67
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    57 (49.5 to 64.5) 58.7 (50.1 to 64.4) -
    Gender categorical
    Units: Subjects
        Female
    109 104 213
        Male
    42 40 82

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    Control - TNF Inhibitor

    Reporting group title
    Experimental
    Reporting group description
    Experimental (Rituximab)

    Primary: Mean change in DAS 28 between 0 and 12 months

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    End point title
    Mean change in DAS 28 between 0 and 12 months
    End point description
    End point type
    Primary
    End point timeframe
    mean change in DAS 28 between 0 and 12 months.
    End point values
    Control Experimental
    Number of subjects analysed
    151
    144
    Units: 295
        median (confidence interval 80%)
    12.71 (12.6 to 12.8)
    12.63 (12.55 to 12.73)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    The analysis of the primary outcome was carried out on the Per Protocol (PP) population. The primary outcome measure was the mean change in DAS28 between 0 and 12 months.
    Comparison groups
    Control v Experimental
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.192
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.513
         upper limit
    0.13

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were followed until resolution or for at least 30 days after discontinuation of study medication, whichever came first.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    Control - TNF Inhibitor

    Reporting group title
    Experimental
    Reporting group description
    Experimental (Rituximab)

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Not collected for this study.
    Serious adverse events
    Control Experimental
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 151 (21.19%)
    37 / 144 (25.69%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Surgical and medical procedures
    Abdominal hernia repair
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shoulder arthroplasty
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fusion surgery
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal laminectomy
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    endometrial cancer
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 151 (1.32%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi organ failure
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Immunoglobulins decreased
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation / Loss of Consciousness
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain assessment
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 151 (1.32%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 151 (1.32%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic polyp
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 151 (1.99%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 151 (1.32%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 151 (1.32%)
    3 / 144 (2.08%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral tonsillitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    Control Experimental
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 144 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2010
    1. Collection of blood for Bio-bank at three and six months The protocol (Study Flow chart) was amended to reflect blood sampling for the bio-bank at 3 and 6 months. 2. Patient Information Sheet was amended to reflect the changes to the blood sampling component.
    08 Feb 2010
    Amendment to Patient Information Sheet – has been amended on at the request of the Sponsor to include more detailed information about the risk of developing the very rare condition, Progressive Multifocal Leukoencephalopathy. Following documents were enclosed with the amendment: • Final ORBIT Patient Information Sheet V2, 16/12/2009 with changes highlighted • Final ORBIT Patient Information Sheet V3, 6/01/2010
    19 Mar 2010
    Amendment to study requirement – collection of additional 30mls of blood at baseline, 3 and 6 months for epigenetic analyses in 50 patients. The protocol was changed on Page 15 to reflect this. The PIS was amended on page 3 to reflect the above. Following documents were enclosed with the amendment: • Protocol V2.1 dated 03/02/2010 with changes highlighted • PIS V3.2 dated 11/02/2010 with changes highlighted
    20 Jul 2010
    Removal of existing sites: • Perth Royal Infirmary • Victoria Infirmary Glasgow • Dumfries & Galloway Royal Infirmary Additional site added: • University of Newcastle Change of PI at existing sites: • Aberdeen • Ayr Hospital
    10 Feb 2011
    1. Temporary halt. A temporary halt to the study was needed to allow the Sponsor to review the merit of the study following a substantial update of the Rituximab SmPC; as a result of EMA not granting approval. As a result a change to the Patient Information Sheet was also required. The temporary halt was submitted to both Ethics and MHRA. 2. Change to PIS V.3.5. The following was included into new PIS V3.5: “Are there any risks involved in taking part? In Europe, the European Medicines Agency (EMA) is responsible for assessing the risks and benefits of drugs. At the moment, it has decided that in routine clinical practice, patients with rheumatoid arthritis who have failed to respond to second line drugs should be treated with anti-TNF drugs (rather than rituximab). This is because there is uncertainty about whether rituximab is as safe and effective as anti-TNF therapy – in technical terms; the EMA says ‘the benefit-risk balance of switching directly to rituximab is at present not settled.’ However, the EMA has decided that rituximab is a safe and effective treatment for patients with rheumatoid arthritis who have failed to respond to anti-TNF therapy. No research has been done to directly compare the risks and benefits of rituximab and anti-TNF therapy. It is possible that rituximab is better, as good; or worse than anti-TNF therapy, and this study will help to find this out.”
    03 Mar 2011
    Uplift of temporary halt
    02 Aug 2011
    Addition of sites, the following sites have been added: • Poole Hospital NHS Trust • Ipswich Hospital NHS Trust • Plymouth Hospitals NHS Trust • South Devon Healthcare NHS Foundation Trust • West Suffolk Hospitals NHS Trust • University Hospitals Coventry and Warwickshire NHS Trust • Royal Devon and Exeter NHS Trust • Betsi Cadwaladr University Health Board • Royal Cornwall Hospitals Trust • South London Healthcare NHS Trust • Barking, Havering & Redbridge University Hospitals NHS Trust, Queens Hospital and King George Hospital • University Hospital of Wales. • Basildon and Thurrock University Hospital NHS Trust • West Herts Hospital NHS Trust • The Countess of Chester Hospital NHS Foundation Trust Protocol – clarification and minor amendments. New protocol – Protocol V2.2 dated 25/04/2011 Change of Sponsorship – Addition of University as co-sponsor.
    16 Aug 2011
    Amendment to Patient Information Sheet: (PIS V4.0 dated 22/06/2012). Included: “As with all therapies for arthritis, very serious side effects can occur rarely with either anti-TNF or Rituximab. For instance, some patients treated with Rituximab have developed allergic reactions, which rarely have proved have proved fatal. Similarly, some patients treated with anti-TNF therapy have developed severe infections that rarely have proved fatal.”
    26 Sep 2011
    Change of co-sponsorship agreement: the University of Glasgow will now act as co-Sponsor for the above study.
    22 May 2013
    1. Addition of sites: • Salisbury NHS Foundation Trust • The Royal Wolverhampton Hospitals NHS Trust • University Hospitals Leicester • Oxford University Hospitals NHS Trust • Southend University Hospitals NHS Foundation Trust • Trafford Healthcare NHS Trust • University Hospitals of Morecambe Bay NHS Foundation Trust • Mid Staffordshire NHS Foundation Trust • The Pennine Acute Hospitals NHS Trust • Kettering General Hospital NHS Foundation Trust • Hairmyres Hospital – NHS Lanarkshire Change of PI: • Change of PI at Countess of Chester Hospital NHS Foundation Trust. • Change of PI at Raigmore Hospital , Inverness. • Change PI Hertfordshire. 2. Change to protocol: • point of clarification. New protocol Version 2.3 -01/10/2012 Exclusion criterion: “Current inflammatory joint disease or autoimmune disease other then RA”, changed to “Current inflammatory joint disease or autoimmune rheumatic disease other then RA” • Use of blood urine samples for future use 3. Change to Reference Safety Information
    10 Jun 2013
    Extension request to the study.
    06 Jun 2014
    Update to Reference Safety Information

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Jan 2011
    A temporary halt to the study was needed to allow the Sponsor to review the merit of the study following a substantial update of the Rituximab SmPC; as a result of EMA not granting approval.
    27 Jan 2011

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27197690
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