Protocol Title : A Randomised, open labelled study in anti ... - EME

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Protocol Version 3 14/01/2013 participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study The PI reserves the right to exclude patients at his centre if they have concerns regarding compliance with the study procedures or any other aspect of the study eligibility not necessarily limited to the above exclusion criteria. 3.4 Criteria for Premature Withdrawal 3.4.1 Subject Withdrawal Criteria A subject may withdraw from the study at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons. 3.4.2 Subject Withdrawal Procedures If subjects prematurely discontinue the study, additional subjects may be enrolled as replacement subjects and assigned to the same treatment sequence at the discretion of the Sponsor. A final visit assessment will be made if the patient agrees. 4 INVESTIGATIONAL MEDICINAL PRODUCT 4.1 List and definition of each IMPs Rituximab Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and heavychain variable region sequences. Tocilizumab Tocilizumab humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology 4.2 Formulation of IMP Rituximab Rituximab is available as 50ml single-use vials containing 500mg rituximab for infusion (10mg/ml) Rituximab is a clear, colourless liquid Tocilizumab Tocilizumab is available in 20mg/ml vials in a concentrate for intravenous infusion. The vials are available in 4ml (80mg), 10ml (200mg), and 20ml (400mg). 4.3 IMP Supply Rituximab Rituximab will be prescribed according to NICE guidelines and thus will be sourced from the NHS supply at each site. Tocilizumab Tocilizumab will be prescribed a according to NICE guidelines and thus will be sourced from the NHS supply at each site. 4.4 Prescription of IMP Rituximab Rituximab will be prescribed by a physician as a member of the study team, using standardised prescription forms. A copy of all prescription forms will be provided to the monitor. Study: R4RA EudraCT: 2012-002535-28 18 / 34
Protocol Version 3 14/01/2013 Tocilizumab Tocilizumab will be prescribed by a physician as a member of the study team, using standardised prescription forms. A copy of all prescription forms will be provided to the monitor. 4.5 Preparation and Administration of IMP 4.5.1 Rituximab Preparation will be performed by a suitably trained member of the study team as per local policy Instructions for Dilution and Suitable Diluent: • Aseptically withdraw 1000mg (100ml) of rituximab. • Slowly add the total volume of rituximab (100mls) to a 500ml bag of sodium chloride 0.9%. To mix, gently invert the bag in order to avoid foaming. Do not shake. • The final concentration of the drug should be between 1-4mg/ml (in this case it will be 1.67mg/ml). • Care must be taken to ensure the sterility of the prepared solution – aseptic technique must be observed. • Inspect the bag visually for any particulate matter and discolouration prior to administration – discard the solution if observed. • The prepared infusion should be used immediately. Method and Rate of Administration: Pre-medication should be prescribed and administered 30 minutes prior to the start of infusion: Drug Dose Route Frequency Methylprednisolone 100mg IVI Stat Chlorphenamine 10mg IVB Stat Paracetamol 1000mg PO Stat Observations e.g. temperature, blood pressure, pulse and respiratory rate should also be carried out prior to the start of infusion. Using IV Volumat Pump The Rituximab entry in the pump library defaults to 1000mg in 600ml (as described above) and defaults to an initial rate of 50mg/hr (30mls/hour). First infusion of each course IV infusion: Initial rate: 50 mg/hr (30mls/hour); increase rate by 50 mg/hr (30mls/hour) every 30 minutes if tolerated, to a maximum of 400 mg/hr (240mls/hour). Rate – mg/hour Rate – mls/hour Initial rate 50mg/hour 30mls/hour After 30mins (if tolerated) 100mg/hour 60mls/hour After 30mins (if tolerated) 150mg/hour 90mls/hour After 30mins (if tolerated) 200mg/hour 120mls/hour After 30mins (if tolerated) 250mg/hour 150mls/hour Study: R4RA EudraCT: 2012-002535-28 19 / 34
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Protocol Title : A Randomised, open labelled study in anti ... - EME

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