Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial

Abstract

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called “JAK/STAT inhibitors”) have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.MethodsThe GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.DiscussionPragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.Trial registrationClinicalTrials.gov, NCT02585258. Registered on 20 October 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2396-3) contains supplementary material, which is available to authorized users.

Cardiometabolic comorbidities in RA and PsA: lessons learned and future directions

“…Furthermore, in patients with active disease, some of these effects might be counteracted by the anti-inflammatory benefits of these drugs, such as a treatment-mediated reduction in underlying inflammation and improvement of mobility. To help address this question, a trial is underway (the Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis Study (GLORIA) trial) to assess the safety profile of low doses of the corticosteroid prednisolone in patients with RA 115 . Notably though, in a previous study, high doses of prednisolone (≥8mg daily) increased the cardiovascular mortality of patients with RA (HR 2.27 (95% CI 1.36-3.79), even after adjusting for propensity to receive glucocorticoids 116 .…”

Association Between Participant Retention and the Proportion of Included Elderly People in Rheumatology Trials: Results From a Series of Exploratory Meta‐Regression Analyses

“…As there is no other evidence concerning elderly patients and retention in rheumatology, further research is warranted. Data from the currently running GLORIA trial, which explicitly includes real‐world elderly RA patients, might eventually shed a brighter light on this issue (17).…”

“…This study is part of the Glucocorticoid Low‐dose Outcome in Rheumatoid Arthritis (GLORIA) project and trial (http://www.gloriatrial.org/) (17). It conforms to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines (for the PRISMA checklist, see , available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24051/abstract) (18).…”

Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people

“…This study is part of the GLORIA project and trial (Glucocorticoid low-dose outcome in rheumatoid arthritis study; http://www.gloriatrial.org/; registered on http://clinicaltrials.gov/; identifier NCT02585258). [24] It conforms to the PRISMA (for systematic reviews of interventional studies) and MOOSE (for systematic reviews of observational studies) guidelines (see supplementary file for research checklists). [25,26] The prespecified protocol (see supplementary file) was preregistered with the protocol registry for systematic reviews, PROSPERO (CRD42018085409).…”

“…[37,38] The current meta-analysis was performed under the umbrella of the GLORIA project, which also includes a trial focusing specifically on RA patients aged 65 or over. [24] While studies aimed at younger populations might measure outcomes and define endpoints that are less relevant to elderly people, performing trials focused on the elderly is an option. This option takes into consideration that some outcomes are particularly valuable for older patients.…”