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

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! • • Pain score using the VAS system Patients will have disease activity and pain score assessed at baseline and monthly • • • • • thereafter for 12 months Physical function (HAQ) will be assessed at 0, 3, 6, 9 and 12 months SF-36 will be assessed at 0, 3, 6, 9 and 12 months FACIT - Fatigue Questionnaire will be assessed at 0, 3, 6, 9 and 12 months Adverse reactions Concomitant medication Data will be entered in the electronic CRF by the Investigator or designee who will also coordinate data validation checks and query resolution. The study visit schedule for patients recruited to this study, who successfully pass screening, will commence from the date of first therapeutic infusion. Monthly follow up visits (+/- 1 week). - Visit: baseline, 1, 2 3, 4, 6, 9, 12, 13 and 14 will also include an US assessment of limited joint set - Visit: baseline, 12 and 14 will include plain x-rays of both hands and feet - Visit: Screening, 6 months and 24 months patients will have fasting lipids and cholesterol measured. As per normal clinical practise, patients with active Rheumatoid arthritis with an unfavourable lipid / cholesterol profile will be initiated on a statin prior to commencing a biological agent. Patients will have this profile repeated at 6 months and at the end of the study. 5.9.1 Unscheduled Visits While patients will be encouraged to attend for the normal visit schedule, unscheduled visits will be undertaken if the patient is unwell or there are any concerns as to the patient’s progress. This will constitute data collection as per routine follow up as per visit 3 5.9.2 Withdrawal of Patients All patients have the right to withdraw consent at any time without prejudice. At the time of withdrawal of consent, a full efficacy and safety evaluation should be performed if patient consents. Withdrawn trial subjects will not be replaced. 5.10 Study Outcome Measures Clinical outcomes Patients will be assessed clinically using the CDAI (Clinical disease activity index), DAS 28 (CRP), Health assessment questionnaire and the Short Form 36 as described below. • CDAI The components of the CDAI (Clinical disease activity Index) are tender joints (28 joint count), the number of swollen joints (28 joint count), a Patient global health index (10 cm VAS) and physician global health index (10 cm VAS). This provides an assessment of Rheumatoid disease activity on a scale form 0-76. CDAI scores High disease activity: >22 Moderate disease activity: 10.1 - 22 Low disease activity 2.8 - 10 Remission < 2.8 Non-responders – CDAI improvement of less than 50% from baseline. Patients may be deemed non-responders at the discretion of the treating physician if they have achieved a CDAI response of > 50% from baseline but have not reached low disease activity (CDAI of 10 or less) Patients showing initial clinical response by 4 months may be subsequently classified as a secondary failure at subsequent study visits if their change in CDAI from baseline is < 50% at any subsequent follow up visit. Patients deemed treatment failures, would be randomised to one of the either therapeutic options. Failure of a second biological therapy after 4 months follow up, would permit the patient to receive the last remaining treatment option. Study: R4RA EudraCT: 2012-002535-28 24 / 34
! Small response - CDAI50 ≥ 50% improvement form baseline assessment Moderate response - CDAI ≥ 75% improvement form baseline Good response – CDAI ≥ 85% improvement form baseline • Disease Activity Score The primary measure of disease activity in this study is the DAS28(CRP). The components of the DAS28(CRP) are the number of tender joints (28 joint count), the number of swollen joints (28 joint count), a Global Health index (100 mm VAS), and the CRP (in mg/L). The formula for determining the DAS28(CRP) is as follows: DAS28(CRP) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.36*ln(CRP+1) + 0.014*GH (VAS) + 0.96 The following 28 joints will be assessed for tenderness in response to pressure or passive motion: Finger Proximal Interphalangeal Joints (8), thumb Interphalangeal joint (2), metacarpophalangeal (MCP) (10), wrists (2) (includes carpometacarpal, intercarpal, and radiocarpal), elbows (2), shoulders (2), and knees (2). DAS 28 Response criteria Non-responders – patients will be designated non-responders if their DAS28 has not improved by > 1.2 from baseline six months after treatment; patients will not be re-treated with their current therapy and will be switched to the other agent (e.g. Rituximab to tociluzimab or visa versa). At the discretion of the patient’s rheumatologist, a patient may be designated a non-responder if their DAS28 has improved by >1.2, but their DAS28 remains above 5.1. Partial responders – patients will be designated partial responders if their DAS28 improves by >1.2 from baseline but remains >3.2. Good responders – patients will be designated good responders if their DAS28 falls by >1.2 to a level 1.2 > 5.1 Patient may be designated a non-responder at the discretion of the rheumatologist > 1.2 > 3.2 but < 5.1 Partial responder. > 1.2 < 3.2 but > 2.6 Good responder. > 1.2 < 2.6 Remission • Health Assessment Questionnaire The HAQ is usually self-administered, but may also be given face-to-face in this clinical study. The Disability Index consists of eight categories assessed by the Disability Index are 1) dressing and grooming, 2) arising, 3) eating, 4) walking, 5) hygiene, 6) reach, 7) grip, and 8) common daily activities. For each of these categories, patients report the amount of difficulty they have in Study: R4RA EudraCT: 2012-002535-28 25 / 34
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Protocol Title : A Randomised, open labelled study in anti ... - EME

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