Adalimumab Drug Optimisation in Rheumatoid Arthritis Using Therapeutic Drug Monitoring

Study Overview
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Brief Summary
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Several prior studies have shown that dose reduction of Tumor Necrosis Factor (TNF)-inhibitors like adalimumab is possible in substantial number of rheumatic disease patients without an increase in disease activity. Biologic therapy is expensive, and is associated with patient burden as dose dependant risk for serious infections . A dose reduction will decrease the risk of side effects and result in substantial cost savings. Currently, most clinicians use Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI) to monitor dose tapering strategies. Although this approach is cost-effective, it might be improved by information on the extent of drug levels, as several studies have shown that adalimumab drug levels are associated with clinical outcome. Therefore, a study comparing dose reduction strategy using drug concentration with dose reduction strategy using disease activity is timely

Detailed Description
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Since the introduction of biologics in rheumatology, as well as treat-to-target (measuring disease activity and adapting treatment accordingly) the prognosis of patients has improved substantially. Obviously, patient burden due to self-injection or infusion, the risk of adverse events and costs demand responsible use of these agents. Multiple studies have shown that a large proportion of patients with rheumatoid arthritis with stable low disease activity can taper their dose or stop without relapse of disease activity. This can be done by using disease activity guided tapering. Drawbacks, however, include increased risk for short lived flares, the effort of slowly and carefully tapering, and somewhat more risk of radiographic damage due to higher mean disease activity. As most biologics are characterized by wide variation in pharmacokinetics between patients, therapeutic drug monitoring (TDM), i.e. dose based on serum trough concentration, might be an attractive approach to lower the dose quickly while remaining clinical efficacy. Although some data suggest that the minimal effective concentration varies between patients, we demonstrated in an earlier study that serum adalimumab concentration of 5 mg/L is enough for initial response to adalimumab. In the first phase of treatment, drug concentration must be high enough to control immunogenicity. To control disease activity after 28 weeks, lower concentrations than 5 mg/L are probably sufficient. Since around 70% of the patients have an adalimumab concentration above 5 mg/l, we assume that dose reduction to achieve these lower targets (for example direct doubling of interval in patients with levels > 10 mg/L) will result in the lowest effective drug dose. Our study group illustrated in 2018 that dose reduction by extending the dosing interval with 50% is non inferior to continuation of standard dose in patients with adalimumab levels > 8mg/L. In other words, measuring drug concentrations can help clinicians to select overexposed patients to reduce the dose of adalimumab without adversely affecting clinical efficiency. We posit that therapeutic drug monitoring can attribute to a more efficient dose reduction strategy. Since steady state drug concentrations are achieved within 16 weeks of treatment, we expect that the dose can be reduced from this point. This is earlier in treatment compared to the strategy using disease activity alone, namely after 6 months of treatment. Conceptually, such a test can improve disease activity guided dose reduction in two ways: 1) flaring caused by empirical tapering (i.e. through trial and error) below the minimal effective concentration would be avoided, and 2) patients can be directly given their minimum effective dose instead of empirical tapering, thereby saving time and drugs. Our aim is to investigate whether the use of drug levels can attribute to a more efficient dose reduction strategy of adalimumab in patients with RA. In this study we will compare costs and clinical efficiency of two dose reduction strategies: a strategy using drug concentration versus a strategy using disease activity scores. We expect that direct medical costs will be lower in the 'drug concentration guided' strategy because: 1) overexposed patient can reduce the dose more timely and, 2) adalimumab dose can be further reduced after 6 months of treatment since we posit that adalimumab concentration of 2 mg/L is sufficient to control disease. In this multi-centre, randomised, open-label trail we will evaluate whether dose reduction of adalimumab using drug concentration can reduce medical costs compared to a strategy using disease activity scores. Furthermore we will evaluate the clinical efficiency of these two strategies. Patients with a good or moderate EULAR response to adalimumab will be randomised to adalimumab dose reduction strategy using drug concentration or disease activity scores. Patients in the 'drug concentration guided' group will reduce adalimumab dose by prolonging the dose-interval using TDM algorithm (a new developed algorithm is used to determine the interval prolongation for each patient). The dose reduction will start at week 16 if trough drug level is higher than 5mg/L, aiming a drug level of 5mg/L in week 16 until 28 and a drug level of 2mg/L from week 28 until week 52. In the initial 16 weeks patients are treated with adalimumab at registered dose of 40mg every other week. Patients in the 'disease activity guided' group will reduce adalimumab dose at week 28 if DAS28-CRP is lower than 2.9. This dose reduction will be attained by extending the dosing interval to every 3 weeks in weeks 28 until 40 and to every 4 weeks from week 40 until week 52. Patients who successfully prolonged the dose interval to 40 mg every 4 weeks in the 'disease activity guided' group and patients who successfully prolonged their dose-interval and achieve a serum concentration of 2.0 mg/L in the 'drug concentration guided' group will be approached to participate to the extension phase (week 52-80). After informed consent is obtained patients will discontinue adalimumab and they will be followed up to week 80. Data regarding disease status, functioning, adalimumab serum concentrations, anti-drug antibodies and medical costs will be collected during this study.

Official Title
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Adalimumab Drug Optimisation in Rheumatoid Arthritis Using Therapeutic Drug Monitoring (ADDORA): Multi-centre Open Label Randomised Controlled Trail

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Diagnostic Test: Adalimumab serum trough concentration
* Diagnostic Test: Disease activity
* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rheumatoid arthritis patient, according to ACR 1987 or ACR/EULAR 2010 criteria; Starting adalimumab as the first biological therapy Who has agreed to participate (written informed consent); Age 18 years or older. Exclusion Criteria: 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; Other disease that might flare if adalimumab is tapered like psoriasis, inflammatory bowel disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Rheumatoid arthritis patients treated with adalimumab will be randomly assigned to a dose reduction strategy using disease activity scores or to a dose reduction strategy using serum drug concentrations
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concentration guided dose reducion<br>Dose reduction of adalimumab will be based on adalimumab through concentration after 16 weeks of treatment with adalimumab. | Diagnostic Test: Adalimumab serum trough concentration<br>* Dose reduction based on adalimumab serum trough concentration<br>Drug: Adalimumab<br>* Adalimumab<br>|
| Active Comparator: Disease activity quided dose reduction<br>Dose reduction of adalimumab will be based on disease activity after 28 weeks of treatment with adalimumab | Diagnostic Test: Disease activity<br>* Dose reduction based on adalimumab diseas activity<br>Drug: Adalimumab<br>* Adalimumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Medical costs | Direct medical costs associated with adalimumab dose reduction using drug concentration versus using disease activity scores | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean time weighted DAS28-CRP | Difference in mean time weighted DAS28-CRP | at 16, 28, 52 and 80 weeks | 
| Direct medical costs | Direct medical costs (medication, visits, cost TDM testing) at the separate time points | at week 28 and week 80 | 
| Indirect medical costs | Costs due to RA-related work absenteeism and presentism for patients with paid jobs and days of inactivity for patients without a paid job. Indirect costs will be estimated by three-monthly questionnaires, monitoring these items in the previous month (based on the SF-HLQ). | at 28, 52 and 80 weeks | 
| Patients with DAS28-CRP<2.9 | Percentage of patients with DAS28-CRP<2.9 | at 52 and 80 weeks | 
| Number of flares |  | at 52 and 80 weeks | 
| Number of dose-interval shortenings |  | at 52 and 80 weeks | 
| Drug levels | The difference in drug levels between the measured drug level and the predicted drug level with the (newly developed) algorithm at different timepoints | at 4,16, 28, 40, 52 and 80 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adalimumab, Rheumatoid arthritis, Therapeutic Drug Monitoring, Drug level, Dose reduction