Concentration-guided dose reduction versus standard dosing in tocilizumab-treated rheumatoid arthritis patients: a randomised, international, multicenter, non-inferiority trial (TODORA)

All patients diagnosed with RA and treated with tocilizumab sc receive the same
dose, so treatment with expensive biologicals is currently based on a *one size
fits all* approach. Our unpublished data showed that this standard dosing
regimen results in a wide range of serum concentrations (from 0-35 mg/L). In
the search to optimize the dose for individual patients, it was demonstrated
that serum levels of tocilizumab of 1 mg/L are adequate to block the IL-6
receptor systemically, as indicated by a reduction in CRP level to normal in
patients with these low trough concentrations. Given the median tocilizumab
concentration of 24 mg/L after 28 weeks of treatment, a substantial proportion
of patients is likely to be overexposed to tocilizumab. This overtreatment is a
waste of health care resources and might be associated with an increased risk
of adverse events, mainly infections. We believe that we can reduce the
overexposure effectively by making use of the drug concentrations found in the
blood of individual patients.

This study has been transitioned to CTIS with ID 2025-520513-30-00 check the CTIS register for the current data.

We aim to optimize the treatment of rheumatoid arthritis patients using
concentration measurements. By doing this we hope to reduce the overexposure to
the drug, save costs and reduce the number of adverse events, especially
infections. The goal of this multicenter trial is also to gain more knowledge
on Therapeutic Drug Monitoring (TDM) in general and create more awareness among
both patients and rheumatologists. This will hopefully result in a succesful
implementation of TDM in clinical practice once it has proven to be effective.

This study is a 52 weeks non-inferiority, multicenter, international,
randomized controlled study in rheumatoid arthritis patients treated with
subcutaneous tocilizumab 162 mg weekly for at least the last 6 months. Several
centers will approach eligible patients and invite them to participate in the
study. After informed consent is obtained during the baseline visit, blood will
be drawn to measure drug trough concentrations. Patients with a tocilizumab
concentration above 15 mg/L will be randomly assigned to dose reduction by
increasing their dosing-interval from once every week to once every two weeks,
or to continuation of their tocilizumab dose (standard dose). Patients with
concentrations below 15 mg/L during the first study visit will not be
randomized and all continue standard treatment.

Patients will be followed for a period of 52 weeks. Data regarding disease
status and functioning will be collected during the baseline visit, and 12, 28,
40 and 52 weeks thereafter. Due to the limited amount of resources of this
study, participating centers may choose to cancel visit 40, resulting in a
total of four visits instead of five. Also, patients with a concentration of <
15 mg/L during the baseline visit will be asked to complete only one follow-up
visit at 52 weeks instead of four follow-up visits. visits instead of five.

After patients have agreed to participate in the study, they will be asked
whether or not they would like to participate in the part of the study were the
finger prick developed by Sanquin (Amsterdam) will be validated to measure drug
levels of tocilizumab. This will comprise performing three finger pricks
additional to the blood that is drawn already during the study. These finger
pricks will be performed during the visit at week 12 with the help of a nurse,
and at home during the two weeks after this visit. Data from the finger prick
will also be used to collect additional information about the drug levels of
tocilizumab, which will be used in the pharmacokinetic analyses.

All patients with a tocilizumab concentration above 15 mg/L will be randomised,
and those patients that are allocated in the intervention group will reduce the
dose by prolonging the dose-interval from 162 mg weekly to 162 mg every two
weeks. This dose reduction will start after the baseline visit and will be
maintained until 52 weeks of follow-up. After the end of the study, the
treating rheumatologist will discuss with the patient whether it is desirable
to maintain on this alternative dosing regimen. Patients allocated to the
control group will not taper their tocilizumab treatment, as this is not
current practice and limited data on tocilizumab tapering is available.

We hypothesize that patients with high tocilizumab concentrations can prolong
their dose interval while maintaining stable disease activity. However, an
increase in disease activity cannot be excluded. If this happens, patients that
started tapering will return to the standard dose. Previous studies showed that
disease activity can be controlled adequately after this dose adjustment. By
participating in the study, patients might also experience burden from the
additional blood that will be obtained. The amount of blood drawn from the
patients will therefore be as little as possible.