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

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Protocol Version 3 14/01/2013 5 STUDY PROCEDURES 5.1 Informed Consent Procedures Written informed consent will be obtained from each patient by the principal investigator or designee. Informed consent will be prepared according to NRES and study sponsor requirements for informed consents. Patients who are candidates for the study must sign an informed consent prior to any study-specific procedures being performed, including any study specific screening procedures 5.2 Screening Procedures Patients may be screened up to 6 weeks prior to recruitment. Prior to screening patients will sign a study specific consent form. Screening will entail evaluation of inclusion and exclusion criteria, clinical examination DAS 28 assessment, study safety blood (FBC, Ig, UE, LFT, ESR, CRP) and TB screening according to local guidelines. 5.3 Randomization Procedures Patients will be stratified (3 strata based on B cells) and randomised within blocks (1:1), with random block size of 6 and 4. Allocated treatment will be revealed by database once eligibility has been confirmed and patient is entered into trial. The local principal investigator/research nurse will log-in to a secure web application (app) and confirm patient eligibility before they can randomise. The web app will check eligibility and subsequently allocate a randomisation number (study number). This ensures that neither the patient nor the clinician can choose whether or not to enter a trial depending on the next allocation. This part of the randomisation system will be written by the Cancer Prevention Trial Unit (CPTU) Database Programmer. The randomisation list will be prepared by the CPTU Statistician and securely embedded with the application code so that it is not accessible to end users or anyone other than the Database Programmer and a limited number of information support staff who have access to all systems. Once a participant has been allocated a treatment, there is an audit trail that prevents anyone from changing the allocation or pretending that no allocation had been made. 5.4 Schedule of Treatment for each visit Patients randomised to tocilizumab will have a monthly infusion at each of the study visits along side their routine assessment. Patients randomised to Rituximab will have 6 monthly infusions of the therapy but will continue to have monthly visits for disease assessment and study specific bloods. 5.5 Study visit schedule Study: R4RA EudraCT: 2012-002535-28 22 / 34
Protocol Version 3 14/01/2013 a - IGRA may not be performed depending upon local guidelines with respect to Latent TB screening for Rituximab and Tocilizumab. b - a pregnancy test will be performed at each study visit for female patients of child bearing age irrespective of the use of contraceptive methods. c - a baseline synovial biopsy is mandatory as part of the patient stratification process however subsequent synovial biopsies will require consent and will remain optional. Patients not receiving a subsequent biopsy will continue within the study as per protocol. 5.6 Screening During the screening visit, written informed consent will be obtained from all patients by the principal investigator or his/her designee before any protocol-specific procedure is performed. Study details, risks and benefits will all be reviewed and subjects will be encouraged to ask questions and clarify any concerns. A chest radiograph will be performed prior to starting any biological therapy, in keeping with local guidelines (unless a chest x-ray had been done in the preceding 3 months and the patient has not had any pulmonary symptoms since then). 5.7 Biopsy visit Patients will receive a synovial biopsy between 1 to 3 weeks prior to their baseline visit. Patients will have the following assessments recorded prior to the synovial biopsy at this visit: • DAS 28 • CDAI • Pain VAS • Routine clinical bloods • Study specific bloods • Vital signs • Physical function using the Health Assessment Questionnaire • A pregnancy test performed will be performed in female patients of child bearing age • A Ultrasound examination of the patients joints will be performed prior to the synovial biopsy A baseline synovial biopsy is mandatory as part of the patient stratification process however subsequent synovial biopsies will remain optional. Patients not receiving a subsequent biopsy at 6 months will continue within the study as per protocol. The initial biopsy visit may be combined with completion of the study screening visit if all screening procedures are available and the patients is eligible for enrolment into the study. Patients must be randomised prior to the biopsy being performed. If the completion of the screening and biopsy visit Study: R4RA EudraCT: 2012-002535-28 23 / 34
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Protocol Title : A Randomised, open
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Chief Investigator Agreement Page T
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Contact details: CPTU Contact: Beno
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Protocol Title : A Randomised, open labelled study in anti ... - EME

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