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

Alfons A Den Broeder,Frank Hj Van Den Hoogen,Noortje Van Herwaarden,Bart Jf Van Den Bemt,Aatke Van Der Maas,Johannes W Bijlsma,Ronald F Van Vollenhoven

doi:10.1186/1471-2474-14-299

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)

Highlights

Preliminary, mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with rheumatoid arthritis (RA) without loss of disease control
Pragmatic cost minimalisation studies using non-inferiority designs and decremental cost effectiveness ratio (DCER) will become more mainstream as cost effectiveness in healthcare gains importance
This seems similar between the three most used anti-tumour necrosis factor (TNF) agents infliximab, adalimumab and etanercept, the proportion of patients in whom the drug can be safely tapered seems to depend on the design of the study and context

Summary

Introduction

Preliminary, 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. TNF-blockers are associated with (sometimes dose dependant) adverse effects including injection site reactions, increased risk of infections and non melanoma skin cancer/lymphomas, rare severe adverse events and high costs [1,2,3]. Optimal use of these drugs is warranted, including the right dose for the right patient [4]. This seems similar between the three most used anti-TNF agents infliximab, adalimumab and etanercept (no data are available on certolizumab and golimumab), the proportion of patients in whom the drug can be safely tapered seems to depend on the design of the study and context (especially authorized or higher than authorized dosage, dose reduction or stopping, and in early or established RA)

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