RhEumatoid arthritis REtreatment with ultra-low dose Rituximab: Disease Outcome after Dose Optimization

Rituximab (RTX) is a biological that is registered for use in patients with
Rheumatoid Arthritis (RA). Nowadays, the RTX doses used in clinical practice
are either 2 × 500 mg, 1 × 1000 mg (low-dose) or 2 × 1000 mg (high-dose) at
least every 6 months.
Evidence from several case reports and an observational open label study
suggests the possibility that lower doses of RTX (1 x 100 mg and 1 x 500 mg)
might be sufficient for effective treatment of RA patients. Furthermore, a
lower dose of RTX may be needed for retreatment compared to initial treatment.
Also, similar anti B-cell monoclonal antibodies (ocrelizumab and ofatumumab)
are successfully used in a lower doses than RTX for RA.
Several disadvantages of RTX could be ameliorated by the use of lower doses of
RTX. These include the dose-dependent risk of infection, long infustion time,
infusion related adverse events and high costs. However, the use of very low
doses of RTX for retreatment of RA has never been studied in a randomised
controlled trial, partly because this is not the priority of the pharmaceutical
company that, after all, registered RTX in higher dosages for treatment of
Lymphoma.

To assess the difference in efficacy between two ultra-low doses (1 x 500 mg
and 1 x 200 mg) and standard low dose (1 x 1000 mg) of RTX retreatment on the
change in DAS28-CRP, compared to a pre-specified non-inferiority margin of 0.6,
at 3 and 6 months in patients with RA.

We will perform a pragmatic multicenter randomized controlled non-inferiority
trial. Patients will be randomized into three groups: conventional low dose (1
x 1000 mg RTX) or one of the two intervention groups (1 x 500 mg or 1 x 200 mg
RTX) in a ratio of 1:2:2. Patients, care providers and researchers will be
blinded for allocation. Follow up duration is 6 months for all patients.
Patients will be approached by their treating rheumatologist for participation
in this trial. Three visits will be planned during the 6-month study period:
baseline, 3 and 6 months follow up.

Conventional low dose: 1 × 1000 mg
Patients allocated to the conventional low dose group will receive a single
1000 mg RTX infusion according to the standard protocol for infusion of
rituximab

Ultra-low dose: 1 × 500 mg
Patients allocated in this group will receive a single 500 mg RTX infusion.
This dose will be diluted to the same volume as the usual care infusion to
ensure the blinding of the study.

Ultra-low dose: 1 × 200 mg
Patients allocated in this group will receive a single 200 mg RTX infusion.
This dose will be diluted to the same volume as the usual care infusion to
ensure the blinding of the study.

Normally, patients visit the treating rheumatologist for a regular control of
their rheumatoid arthritis once every three or six months. A blood sample is
taken during a regular visit.
In this study the participants will be scheduled to a visit once every three
months. At the baseline visit, patients are asked for baseline characteristics
and radiographs will be made of hands and feet if no radiographs had been made
in the past three months. Patients are asked to complete a short questionnaire
after the RTX infusion on the occurrence of infusion-related adverse events.
During this first visit, two blood samples will be collected, one before and
one after infusion of the study medication. During the other visits one blood
sample will be collected. In a subgroup of patients (convenient sample who are
willing), an extra blood sample will be taken 1 month after infusion. During
all visits several short questionnaires will be completed: the OMERACT flare
questionnaire, HAQ-DI, EUROQOL-5D-5L and a questionnaire on health related
absenteeism. The extra time required for this study will amount to
approximately 1 hour for the first visit and 15 minutes for the other visits.
This results in a total of 1,5 hours of extra time required for a patient to
take part in the study (excluding travel time).
Risks of participation in this study includes the chance of a temporary
increase in disease activity in the patients receiving a lower dose than they
used to. However, if this happens, the increase in disease activity will be
short-lived as the rheumatologist will act on this. On the other hand, patients
receiving a lower dose of RTX will have a reduced chance on RTX related side
effects.