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Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis.

ABSTRACT: OBJECTIVE:The objective was to determine if dose reduction is non-inferior to full-dose TNFi to maintain low disease activity (LDA) in patients already in remission with TNFi, in axial spondyloarthritis. METHODS:Randomized, parallel, non-inferiority, open-label multicentre clinical trial. Patients were eligible if they had axial spondyloarthritis and had been in clinical remission for ??6?months with any available TNFi (adalimumab, etanercept, infliximab, golimumab) at the dose recommended by product labelling. Patients were randomized by automated central allocation to continue the same TNFi dose schedule, or to reduce the dose by roughly half according to the protocol. The main outcome was the proportion of subjects with LDA after 1?year. Serious adverse reactions or infections were recorded. RESULTS:The trial stopped due to end of the funding period, after 126 patients were randomized; 113 patients (84.1% male, mean age (SD) 45.6 (13.0) years) were included in the main per-protocol subset. Non-inferiority was concluded for LDA at 1?year (47/55 (83.8%) patients in the full-dose and 48/58 (81.3%) patients in the reduced-dose arm, adjusted difference (95% CI) -?2.5% (-?16.6% to 11.7%)). Serious adverse reactions or infections were reported in 7/62 patients (11.3%) assigned to full dose and 2/61 patients (3.3%) assigned to reduced dose (p value?=?0.164). CONCLUSION:In patients with ankylosing spondylitis in clinical remission for at least 6?months, dose reduction is non-inferior to full TNF inhibitor doses to maintain LDA after 1?year. Serious adverse events may be less frequent with reduced doses. TRIAL REGISTRATION:EU Clinical Trials Registry, EudraCT 2011-005871-18 and ClinicalTrials.gov, NCT01604629 .

SUBMITTER: Gratacos J

PROVIDER: S-EPMC6323809 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis.

Gratacós Jordi J Pontes Caridad C Juanola Xavier X Sanz Jesús J Torres Ferran F Avendaño Cristina C Vallano Antoni A Calvo Gonzalo G de Miguel Eugenio E Sanmartí Raimon R

Arthritis research & therapy 20190108 1

<h4>Objective</h4>The objective was to determine if dose reduction is non-inferior to full-dose TNFi to maintain low disease activity (LDA) in patients already in remission with TNFi, in axial spondyloarthritis.<h4>Methods</h4>Randomized, parallel, non-inferiority, open-label multicentre clinical trial. Patients were eligible if they had axial spondyloarthritis and had been in clinical remission for ≥ 6 months with any available TNFi (adalimumab, etanercept, infliximab, golimumab) at the dose re ...[more]

PMID: 30621746

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Project description: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).

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Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis.

Publications

Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis.

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