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Open Access Highly Accessed Study protocol

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

Alfons A den Broeder1*, Noortje van Herwaarden1, Aatke van der Maas1, Frank HJ van den Hoogen1, Johannes W Bijlsma2, Ronald F van Vollenhoven3 and Bart JF van den Bemt4

Author Affiliations

1 Department of Rheumatology, Sint Maartenskliniek, PO box 9011, Nijmegen 6500 GM, The Netherlands

2 University Medical Center Utrecht, Utrecht, the Netherlands

3 The Karolinska Institute, Stockholm, Sweden

4 Department of Pharmacy, Sint Maartenskliniek, Nijmegen, The Netherlands

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BMC Musculoskeletal Disorders 2013, 14:299  doi:10.1186/1471-2474-14-299

Published: 24 October 2013

Abstract

Background

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. However, long term safety, cost effectiveness and feasibility in clinical practice remain uncertain.

Methods/Design

This 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.

Discussion

The 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 registration

Dutch Trial Register NTR3216, The study has received ethical review board approval (number NL37704.091.11)

Keywords:
Rheumatoid arthritis; Dose reduction; Discontinuation; Anti TNF; Spacing; Randomised controlled trial; Non-inferiority; Cost minimalisation; Design; Decremental cost effectiveness ratio (DCER)