Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment (ADDORA-switch)
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|ClinicalTrials.gov Identifier: NCT04251741|
Recruitment Status : Recruiting
First Posted : February 5, 2020
Last Update Posted : October 14, 2020
|Condition or disease||Intervention/treatment||Phase|
|Rheumatoid Arthritis||Diagnostic Test: Adalimumab trough concentration Other: Usual care||Phase 4|
Over the last decades biopharmaceuticals such as agents against tumor necrosis factor (TNF), are frequently prescribed to optimize rheumatoid arthritis treatment. Although TNFi such as adalimumab, etanercept and infliximab, have improved the treatment of rheumatoid arthritis, a proportion of patients discontinue the treatment because of inefficacy or intolerance.
Where TNFi have failed, mainly two treatment approaches are available: switch to another TNFi or to a biological with a different mode of action (notably rituximab, abatacept or tocilizumab) or to a target synthetic DMARDs. The EULAR recommendation for the management of rheumatoid arthritis advocate that any biologic agent including a subsequent TNFi can be used with equal chance for effect in case of non-response to a previous TNFi. This recommendation is based on three randomized controlled trails, but it should be noted that systematic reviews also including non-randomized controlled studies sometimes concluded that non-TNFi are more effective after TNFi failure than a second TNFi.
Of note, currently there are no strong predictors available for response to bDMARDS in RA. This study focuses on non-response after adalimumab, as this is the most prescribed TNFi worldwide.
Although it seems that indeed on a group level response to a non-TNFi is comparable to a second TNFi after the first TNFi has failed, using therapeutic drug monitoring could identify subgroups of patient who would benefit more from either a non-TNFi or a TNF-i as next treatment. The underlying pathophysiological mechanisms for this hypothesis are explored in this study.
Nonresponse on adalimumab in RA can have different causes. Firstly, the patient might not be sensitive to TNF blockade at all, or the patient develops this trait later on (primary nonresponse or secondary nonresponse). In these patients, switching to a non-TNFi might conceptually be superior to starting a second TNFi. However, in other patients nonresponse (either primary or secondary) might be caused by inefficient drug concentration because of development of antidrug antibodies against adalimumab. In these patients a TNFi might be just as effective as a non-TNFi, as these patients have drug- but not class failure. Thus, testing of adalimumab levels might be helpful in channelling patients to their most optimal treatment.
Above mentioned hypothesis has been tested in three studies (5) of which one concerned adalimumab in RA. This study showed that response to a second TNFi was indeed higher in patients with antidrug antibodies (ADA) and low adalimumab levels, and lower in patients with adequate adalimumab levels. However, a diagnostic study comparing a serum concentration guided versus usual care switching strategy has not yet been performed.
In this multi-centre, double blinded randomized controlled trial it will be evaluated whether clinical outcome after switching to a subsequent biological treatment is superior with a switching strategy using adalimumab concentration compared to usual care switching strategy.
Patients with rheumatoid arthritis starting another bDMARD (biologic disease modifying antirheumatic drugs) after adalimumab failure (defined as DAS28-CRP >2.9) are randomly assigned to usual care (with randomized switch to etanercept or to a non-TNFi) or 'drug concentration' guided switch.
Data regarding disease status, functioning, adverse events and use of co-medication/rescue medication will be collected during this study.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||84 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||
Patients with rheumatoid arthritis starting another bDMARD after adalimumab failure (defined as DAS28CRP>2.9) are randomly assigned to usual care (with randomized switch to etanercept or to a non-TNF-inhibitor) or 'drug concentration' guided switch.
When randomized to the usual care group, the treating rheumatologist gets the advice from an independent coworker to switch patients to etanercept 1*50 mg/week or a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab), based on a secondary randomization schedule. When randomized to a non-TNFi, the treating rheumatologist will choose the non-TNFi. In the 'drug concentration guided' group, in patients with a concentration <1.0 mg/L a switch to etanercept (standard dosing regimen of 50mg once a week) is advised by an independent coworker and in patients with a concentration ≥ 1.0 start of a non-TNF-inhibitor (the same drugs and dosing as in usual care group) is advised.
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||Rheumatologists and patients remain blinded for allocation.|
|Official Title:||Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment: a Blinded Randomized Superiority Trial|
|Actual Study Start Date :||March 1, 2020|
|Estimated Primary Completion Date :||February 1, 2022|
|Estimated Study Completion Date :||February 1, 2022|
Active Comparator: Usual care group
Based on a secondary randomization schedule patients are treated with etanercept or a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab)
Other: Usual care
In the usual care group, switch to subsequent biological is based on secondary randomisation
Experimental: 'Drug concentration guided' group
Patients with a concentration <1.0 mg/L switch to etanercept and patients with a concentration ≥ 1.0 start a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab)
Diagnostic Test: Adalimumab trough concentration
In the 'drug concentration guided' group, switching to subsequent biological is based on adalimumab trough concentration
- mean time weighted DAS28-CRP [ Time Frame: 24 weeks ]difference in mean time weighted DAS28-CRP between the two groups
- Good or moderate response according the EULAR response criteria [ Time Frame: 12 en 24 weeks ]Percentage of patients with good or moderate response according the EULAR response criteria
- Minimal disease activity (DAS28-CRP<2.9) [ Time Frame: 24 weeks ]Percentage of patients with minimal disease activity (DAS28-CRP<2.9)
- Non-responders [ Time Frame: 24 weeks ]Percentage of patients with no response according to EULAR response criteria
- Number of adverse events [ Time Frame: 24 weeks ]The number of adverse events
- Severity of adverse events [ Time Frame: 24 weeks ]Severity of adverse events
- Cumulative dose co-medication [ Time Frame: 24 weeks ]Cumulative dose of co-medication
- Times co-medication is used [ Time Frame: 24 weeks ]Number of times co-medication is used
- Cumulative dose of rescue medication [ Time Frame: 24 weeks ]Cumulative dose of rescue medication
- Times rescue medication is used [ Time Frame: 24 weeks ]Number of times co-medication is used
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04251741
|Contact: Sadaf Atiqi, MDfirstname.lastname@example.org|
|Contact: Maike Wientjes, MSc||0031 24 365 email@example.com|
|Ubbergen, Gelderland, Netherlands, 6574NA|
|Contact: Maike Wientjes, Msc 0031 24 365 9180 firstname.lastname@example.org|
|Reade Rheumatology Research Institute||Recruiting|
|Amsterdam, Noord- Holland, Netherlands, 1056AB|
|Contact: Sadaf Atiqi, MD 0031-202421641 email@example.com|
|Contact: Femke Hooijberg, Bsc 0031-202421633 firstname.lastname@example.org|
|Principal Investigator:||Gertjan Wolbink, PhD||Reade Rheumatology Research Institute|
|Principal Investigator:||Alfons A Den Broerder, PhD||Sint Maartenskliniek|