Clinical trial NCT04251741: Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment
Official title: Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment: a Blinded Randomized Superiority Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: Adalimumab
Rheumatoid arthritis
Therapeutic Drug Monitoring
Drug level
Switching
Failure
Non-response
Subsequent biological
Lead sponsor: Reade Rheumatology Research Institute
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Sint Maartenskliniek
First posted: 2020-02-05
Enrollment: 86
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 random allocation. 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.
Primary purpose: TREATMENT

Brief summary: A potential application of therapeutic drug monitoring is to predict efficacy after switch to another biological in the case of inefficacy of the previous TNF-inhibitor (TNFi) in rheumatoid arthritis (RA) patients. It has been shown that when antidrug antibodies against adalimumab are detected (resulting in lower drug serum concentrations) in patients failing adalimumab, a normal response to a next TNF blocker can be anticipated. However, when clinical response is unsatisfactory and no antidrug antibodies against the first TNFi are detected (generally drug levels are adequate in this case), this predicts a lower response to a next TNFi. This means drug resistant failure in the former, compared to class resistant failure in latter category of patients. The current RA treatment strategy after failure of the first TNF-inhibitor is to start either a second TNFi or a non-TNFi. However, by channelling patients with sufficient adalimumab concentration to a non-TNFi will provide higher chance of disease control. Patients with very low or undetectable drug levels have an equal or potential higher chance of disease control with a drug of the same class (i.e. another TNFi).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* rheumatoid arthritis patient, according to American College of Rheumatology (ACR) 1987 and/or EULAR/ACR 2010 criteria;
* recently failed treatment with adalimumab (defined as DAS28-CRP \>2.9) and not treated with a subsequent bDMARD or target synthetic DMARD (tsDMARD)
* Received adalimumab for at least 10 weeks in standard dosing (40mg subcutaneously every other week, either in monotherapy or combined with methotrexate or leflunomide)
* Stop adalimumab due to inefficacy, either alone or combined with side effects
* who has agreed to participate (written informed consent);
* age 16 years or older.

Exclusion Criteria:

* Treatment with another TNF-inhibitor prior to adalimumab
* Treatment with all non-TNFi options (abatacept, rituximab, sarilumab and tocilizumab) prior to adalimumab
* scheduled surgery during the follow-up of the study or other pre-planned reasons for treatment discontinuation
* life expectancy shorter than follow-up period of the study;
* no possibility to safely receive an TNF-inhibitor or a non TNF-inhibitor

Primary outcomes:
measure: mean time weighted DAS28-CRP
timeFrame: 24 weeks
Secondary outcomes:
measure: Good or moderate response according the EULAR response criteria
timeFrame: 12 en 24 weeks
measure: Minimal disease activity (DAS28-CRP<2.9)
timeFrame: 24 weeks
measure: Non-responders
timeFrame: 24 weeks
measure: Number of adverse events
timeFrame: 24 weeks
measure: Severity of adverse events
timeFrame: 24 weeks
measure: Cumulative dose co-medication
timeFrame: 24 weeks
measure: Times co-medication is used
timeFrame: 24 weeks
measure: Cumulative dose of rescue medication
timeFrame: 24 weeks
measure: Times rescue medication is used
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Ubbergen
country: Netherlands
facility: Sint Maartenskliniek
state: Gelderland
city: Amsterdam
country: Netherlands
facility: Reade Rheumatology Research Institute
state: Noord- Holland
Study officials:
affiliation: Reade Rheumatology Research Institute
name: Gertjan Wolbink, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sint Maartenskliniek
name: Alfons A Den Broerder, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cantini F, Niccoli L, Nannini C, Cassara E, Kaloudi O, Giulio Favalli E, Becciolini A, Benucci M, Gobbi FL, Guiducci S, Foti R, Mosca M, Goletti D. Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Semin Arthritis Rheum. 2017 Oct;47(2):183-192. doi: 10.1016/j.semarthrit.2017.03.008. Epub 2017 Mar 22.
citation: Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ; British Society for Rheumatology Biologics Register. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007 Jan;56(1):13-20. doi: 10.1002/art.22331.
citation: Jamnitski A, Bartelds GM, Nurmohamed MT, van Schouwenburg PA, van Schaardenburg D, Stapel SO, Dijkmans BA, Aarden L, Wolbink GJ. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011 Feb;70(2):284-8. doi: 10.1136/ard.2010.135111. Epub 2010 Nov 10.
citation: L' Ami MJ, Ruwaard J, Krieckaert C, Nurmohamed MT, van Vollenhoven RF, Rispens T, Wolbink GJ. Serum drug concentrations to optimize switching from adalimumab to etanercept in rheumatoid arthritis. Scand J Rheumatol. 2019 Jul;48(4):266-270. doi: 10.1080/03009742.2019.1577915. Epub 2019 Apr 23.