Polymyalgia rheumatic
or other conditions requiring systemic treatment with glucocor- ticoids were excluded. Patients with giant cell arteritis (cranial or large vessel) as indicated by unequivocal clinical symptoms, imaging or biopsy results were excluded; however, screening by imaging or biopsy was not mandated as this currently does not reflect clinical practice. 7 Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Randomisation and masking Patients were randomly assigned to one of two groups in a 1:1 ratio. One specific aspect in PMR-SPARE was the blinding towards acute phase reactants, since inhibition of the IL-6 receptor by tocilizumab would strongly impact CRP and ESR levels and therefore could indirectly unblind treatment alloca- tion. This could also increase the risk of incorrect rejection of the null hypothesis on the primary outcome of glucocorticoid- free remission if acute phase reactants were part of this assess- ment. The investigators and clinical assessors in the trial were therefore not only blinded to the treatment allocation, but also to the results of CRP and ESR, as well as to other laboratory markers that may have unblinded the group allocation, such as fasting lipids and liver enzymes. A dedicated laboratory assessor in each study centre, who was also blinded to the treatment allo- cation but not involved in any other parts of the study, reviewed the laboratory results. The results were not disclosed to any other investigator. Procedures The ‘tocilizumab’ group received tocilizumab 162 mg as subcu- taneous injection every week; the ‘placebo’ group received matching placebo injections every week. The 24-week double- blind period consisted of a 16-week treatment phase followed by an 8 week follow-up for the assessment of safety and mainte- nance of response. All patients received oral glucocorticoids in conjunction with a rapid tapering scheme starting with 20 mg prednisone at baseline (irrespective of the pre-baseline dose), tapering the daily dose by 2.5 mg every week until a dose of 10 mg has been used for a week; subsequently the daily prednisone dose was reduced to 9mg (week 6), 7mg (week 7), 5mg (week 8), 4 mg (week 9), 2 mg (week 10) and 1 mg (week 11); after week 11, no glucocorticoids were applied per regular scheme. The protocol also included a prespecified treatment regimen for relapse, according to which the prednisone dose was increased by 5 mg for 1 week. If clinical remission was re-achieved, the prednisone dose was tapered at the discretion of the investigator within 4 weeks to the pre-relapse dose; if remission was not achieved, then the prednisone dose was further increased and subsequently tapered at the discretion of the investigator until the pre-relapse dose was reached. Thereafter, the pre-specified tapering protocol was followed again. Outcomes The primary efficacy endpoint was the achievement of glucocorticoid-free remission at week 16. Key secondary effi- cacy endpoints were glucocorticoid-free remission at weeks 12 and 24, time to first relapse and cumulative prednisone doses at weeks 16 and 24. Safety was documented and evaluated for incidence and severity of adverse events in all patients who had received at least one dose of tocilizumab or placebo.
events in up to 65% of patients, including infections, diabetes, hypertension, weight gain, cataracts, glaucoma, osteoporosis and skin changes. 8 Few glucocorticoid sparing agents have been investigated in polymyalgia rheumatica yet with mixed results. Most evidence from randomised controlled trials is available for methotrexate; however, its effect in reducing cumulative glucocorticoid doses and preventing relapses is only moderate at best. 9 Inhibitors of tumour necrosis factor α were ineffective in trials, 10 11 and azathioprine revealed only a small benefit on the daily glucocorticoid dose after 12 months. 12 Given the high risk of adverse events resulting from long-term use of gluco- corticoids in clinical practice, 13 effective glucocorticoid sparing agents are a major unmet need in the management of polymy- algia rheumatica. 14 Given the profoundly elevated levels of IL-6 and the acute phase reactants induced by this proinflammatory cytokine, 15 16 inhibition of the IL-6 pathway constitutes an attractive ther- apeutic approach for polymyalgia rheumatica. Several case reports, case series and open label clinical studies suggested an excellent clinical effect of tocilizumab. While these studies deliv- ered a clear proof of concept, most concluded that randomised controlled trials of IL-6 inhibition in polymyalgia rheumatica are warranted. 17–20 We conducted a double blind, randomised, placebo-controlled clinical trial to investigate the efficacy and safety of tocilizumab compared with placebo in patients with new onset polymyalgia rheumatica receiving background gluco- corticoid therapy. This is a 24-week randomised, double-blind, placebo-controlled, phase 2/3 trial, the polymyalgia rheumatica glucocorticoid sparing (PMR-SPARE) trial, to investigate whether treatment with tocilizumab resulted in higher rates of glucocorticoid- free remission at week 16 compared with placebo, in patients with new onset polymyalgia rheumatica. All patients received a rapid glucocorticoid tapering protocol that allowed confining glucocorticoid exposure to 11 weeks unless a relapse occurred. Safety and efficacy aspects were monitored for 24 weeks (online supplemental table 1). The trial protocol, including the statistical analysis plan, is available in the online supplemental appendix 2. The study is registered at ClinicalTrials.gov. The study was conducted in accordance with Good Clin- ical Practice guidelines and the Declaration of Helsinki. All patients provided their written informed consent. The study was conducted at three centres across Austria (Medical University of Vienna, Medical University of Graz and Hietzing Hospital Vienna). A web-based randomisation algorithm provided by the Medical University of Vienna was used as described in the study protocol. Blinding and treatment allocation was performed by an unblinded study team of the Medical University of Vienna, data base maintenance and monitoring was performed by the Coordination Centre for Clinical Studies (KKS) of the Medical University of Vienna. These investigators were not involved in any other part of the study. METHODS Study design and patients Patients enrolled fulfilled the provisional 2012 European League Against Rheumatism – American College of Rheuma- tology classification criteria for polymyalgia rheumatica at screening and baseline. 21 A clinical diagnosis of polymyalgia rheumatica could have been established up to 2 weeks before the screening visit, during which period a maximum amount of gluco- corticoids at 25 mg prednisone equivalent per day was allowed. Patients with evidence of other inflammatory rheumatic diseases
Bonelli M, et al . Ann Rheum Dis 2022; 81 :838–844. doi:10.1136/annrheumdis-2021-221126
839
Powered by FlippingBook