Dose REduction strategy of subcutaneous TNF inhibitors in rheumatoid arthritis: design of a pragmatic randomised non inferiority trial, the DRESS study

Abstract

BackgroundPreliminary, mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control. However, long term safety, cost effectiveness and feasibility in clinical practice remain uncertain.Methods/DesignThis study is a 18-months pragmatic, non-inferiority, cost minimalisation, randomized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor (TNF) blockers adalimumab and etanercept in RA patients with low disease activity. 180 RA patients with low disease activity (DAS28 < 3.2 or clinical judgment of the rheumatologist) are randomized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker, and usual care. Implementation is done in routine daily care, using treat to target and feedback implementation in both treatment arms. The primary outcome is non-inferiority (NI margin 20%) in cumulative incidence of persistent (> 3 months) RA flare, according to a recently validated DAS28 based flare criterion (DAS28 change > 1.2, or DAS28 increase of 0.6 and current DAS28 ≥ 3.2). Secondary outcomes include mean disease activity, function, radiographic progression, safety and cost effectiveness. Cost per quality adjusted life year (QALY) differences between groups are expressed as a decremental cost effectiveness ratio (DCER), i.e. saved costs divided by (possible) loss in QALY.DiscussionThe design of this study targeted several clinical and methodological issues on TNF blocker dose de-escalation, including how to taper the TNF blockers, the satisfactory control condition, how to define flare, implementation in clinical practice, and the choice of the non-inferiority margin. Pragmatic cost minimalisation studies using non-inferiority designs and DCERs will become more mainstream as cost effectiveness in healthcare gains importance.Trial registrationDutch Trial Register NTR3216, The study has received ethical review board approval (number NL37704.091.11)

Feasibility and Domain Validation of Rheumatoid Arthritis (RA) Flare Core Domain Set: Report of the OMERACT 2014 RA Flare Group Plenary

“…A combined flare definition (patient report of flare and DAS28 increase [DAS scores < 3.2 at second visit required an increase of 1.2 units whereas DAS ≥ 3.2 at second visit required increase of 0.6] (22)) was also evaluated with initial data from the RA-BIODAM, a 10-country LOS to validate biomarkers that predict joint damage and DRESS RCT (Dose Reduction Strategy of Subcutaneous TNF inhibitors in RA) (22). The overall flare rate was 14%; 56% had persisted > 7 days.…”

Long-term outcomes after disease activity-guided dose reduction of TNF inhibition in rheumatoid arthritis: 3-year data of the DRESS study - a randomised controlled pragmatic non-inferiority strategy trial

“…For the primary analysis, we kept the original non-inferiority margin of 20% difference in major flare between DR and UC groups, based on the same reasoning as mentioned before 16. Point estimates with CI (95% CI) of the difference in cumulative incidence of major flare between groups were calculated and the upper limits of the CI were compared with the non-inferiority margin.…”

Disease activity-guided dose optimisation of adalimumab and etanercept is a cost-effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study

“…The rationale and design, and primary outcomes have been described extensively elsewhere12 13 and are summarised here. Consenting patients with RA using adalimumab or etanercept in any stable dose and interval for at least 6 months, with stable low disease activity at two subsequent visits, were enrolled.…”

“…Random sized blocks (block size 3–12) were used, and a ratio of dose optimisation versus control condition is 2:1. For more details, see elsewhere 12 13…”