Using adalimumab serum concentration to choose a subsequent biological DMARD in rheumatoid arthritis patients failing adalimumab treatment (ADDORA-switch): study protocol for a fully blinded randomised superiority test-treatment trial

Maike H M Wientjes,Ronald F Van Vollenhoven,Annick De Vries,Gerrit Jan Wolbink,Theo Rispens,Bart J F Van Den Bemt,Sadaf Atiqi,Michael T Nurmohamed,Maarten Boers,Alfons A Den Broeder

doi:10.1186/s13063-021-05358-7

Abstract

BackgroundA substantial proportion of rheumatoid arthritis (RA) patients discontinues treatment with tumour necrosis factor inhibitors (TNFi) due to inefficacy or intolerance. After the failure of treatment with a TNFi, treatment can be switched to another TNFi or a bDMARD with a different mode of action (non-TNFi). Measurement of serum drug concentrations and/or anti-drug antibodies (therapeutic drug monitoring (TDM)) may help to inform the choice for the next step. However, the clinical utility of TDM to guide switching has not been investigated in a randomised test-treatment study.MethodsADDORA-switch is a 24-week, multi-centre, triple-blinded, superiority test-treatment randomised controlled trial. A total of 84 RA patients failing adalimumab treatment (treatment failure defined as DAS28-CRP > 2.9) will be randomised in a 1:1 ratio to a switching strategy to either TNFi or non-TNFi based on adalimumab serum trough level (intervention group) or random allocation (control group). The primary outcome is the between-group difference in mean time-weighted DAS28 over 24 weeks.DiscussionThe trial design differs in many aspects from previously published and ongoing TDM studies and is considered the first blinded test-treatment trial using TDM in RA. Several choices in the design of this trial are described, and overarching principles regarding test-treatment trials and clinical utility of TDM are discussed in further detail.Trial registrationDutch Trial Register NL8210. Registered on 3 December 2019 (CMO NL69841.091.19).

Highlights

A substantial proportion of rheumatoid arthritis (RA) patients discontinues treatment with tumour necrosis factor inhibitors (TNFi) due to inefficacy or intolerance
The Adalimumab dose optimization in Rheumatoid Arthritis (ADDORA)-switch study will evaluate the additive value of measurement of adalimumab serum concentrations at the moment of failure to adalimumab in determining the subsequent biological in RA patients
The trial design differs in many aspects from previously published and ongoing Therapeutic drug monitoring (TDM) studies and can be considered the first test-treatment RCT using therapeutic drug monitoring in RA

Summary

Introduction

A substantial proportion of rheumatoid arthritis (RA) patients discontinues treatment with tumour necrosis factor inhibitors (TNFi) due to inefficacy or intolerance. After the failure of treatment with a TNFi, treatment can be switched to another TNFi or a bDMARD with a different mode of action (non-TNFi). Tumour necrosis factor inhibitors (TNFi) have improved treatment of rheumatoid arthritis (RA), but a proportion of patients discontinues treatment due to inefficacy or intolerance [1]. After the failure of treatment with a TNFi, two approaches are viable with an equal chance of response: treatment with another TNFi (adalimumab, certolizumab, etanercept, golimumab, infliximab) or treatment with a bDMARD with a different mode of action (non-TNFi: abatacept, rituximab, sarilumab, tocilizumab). It is hypothesised that therapeutic drug monitoring (measurement of drug concentrations and/or anti-drug antibodies, TDM) might help the clinician in choosing between treatment with another TNFi or treatment with a bDMARD with a different mode of action. We focus on the failure to adalimumab, a fully human monoclonal antibody TNFi that is one of the most frequently prescribed TNFi worldwide

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