Adalimumab dose optimisation in rheumatoid arthritis using therapeutic drug monitoring (ADDORA): multi-centre open label randomised controlled trail

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 therapeutic drug monitoring (TDM) with dose reduction strategy
using disease activity is timely

The main objective is to evaluate whether adalimumab dose reduction using
adalimumab serum measurements (TDM strategy) will minimize medical costs,
compared to disease activity guided dose reduction in rheumatoid arthritis (RA)
patients.

This study is a multi-centre, randomised, open-label trail which consists of
three consecutive phases, with a total study duration of 80 weeks:

Phase 1 (week 0 to 16) an observational phase; patients will be treated, in
accordance with current Dutch clinical guidelines, with adalimumab 40 mg every
other week.

Phase 2 (week 16 to 52) randomized, cost-minimization, open trial; patients who
achieved EULAR moderate or good response (15) during phase 1 are randomly
assigned (1:1) to adalimumab dose reduction using drug concentration or disease
activity scores
- Drug concentration-guided group: Dose-interval will be prolonged at week 16
according to the adalimumab serum concentration at week 16, irrespective of
disease activity, targeting at 5 mg/L. A newly developed algorithm (see below)
was used to determine the interval prolongation for each patient. At week 28,
the dose-interval is prolonged further, targeting at 2 mg/L.
- Disease activity-guided group: Patients continue the standard dose up to week
28.Thereafter, the dose interval is prolonged in patients who achieve DAS28-CRP
<=2.9 according to the DRESS-protocol (16).


Phase 3 (week 52-80) extension phase; patients who successfully prolonged the
dose interval to 40 mg every 4 weeks in the disease activity-guided group will
discontinue adalimumab at week 52 and be followed up to week 80. Patients who
successfully prolonged their dose-interval in the drug concentration guided
group and achieve a serum concentration of 2.0 mg/L, will maintain their dose
for another 28 weeks (up to week 80). Serum trough levels do not predict
successful discontinuation of adalimumab, therefore, these patients will
continue low dose adalimumab

- Drug concentration guided group: Dose-interval will be prolonged using
adalimumab serum concentration at week 16,
- Disease activity-guided group: dose interval is prolonged using disease
activity scores.

The main risk associated with this study is an increase of disease activity
with loss of response. Several studies have shown that tapering of bDMARDs is
safe. Furthermore we have already demonstrated that adalimumab concentration of
<5mg/L is sufficient to control disease activity. Stated the increased risk of
overtreatment and higher medical costs, dose reduction appears to be reasonable
in patient with rheumatoid arthritis. Since the main propose of this tapering
study is to optimize treatment, to reduce risk of overtreatment and to reduce
medical cost, we are convinced that the execution of the study exceeds the
burden and risks of this study.