Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial

• Published in: Current controlled trials in cardiovascular medicine 2020-04, Vol.21 (1), p.313-11, Article 313
• Main Authors: van der Leeuw, Matthijs S, Welsing, Paco M J, de Hair, Maria J H, Jacobs, Johannes W G, Marijnissen, Anne C A, Linn-Rasker, Suzanne P, Fodili, Faouzia, Bos, Reinhard, Tekstra, Janneke, van Laar, Jacob M
• Format: Article
• Language: English
• Subjects: Analysis; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antirheumatic agents; Antirheumatic Agents - adverse effects; Antirheumatic Agents - therapeutic use; Arthritis; Arthritis, Rheumatoid - drug therapy; Biological Products; Care and treatment; Cost analysis; Disease; Drug dosages; Drug Therapy, Combination; Glucocorticoids; Glucocorticoids - adverse effects; Glucocorticoids - therapeutic use; Humans; Immunology; Informed consent; Medical research; Monoclonal antibodies; Multicenter Studies as Topic; Netherlands; Patients; Pragmatic Clinical Trials as Topic; Prednisone; Prednisone - adverse effects; Prednisone - therapeutic use; Quality of Life; Remission (Medicine); Remission Induction; Rheumatoid arthritis; Rheumatoid arthritis, Tocilizumab, Prednisone, Randomized controlled trial, Insufficient response to csDMARDs; Rheumatoid factor; Rheumatology; Severity of Illness Index; Study Protocol; Tocilizumab; Treatment Outcome
• ISSN: 1745-6215; 1745-6215
• DOI: 10.1186/s13063-020-04260-y

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Regi