COBRA treat-to-target trial

Recent international guidelines advise to start with methotrexate (MTX) as
early as possible after the diagnosis of rheumatoid arthritis (RA), either
alone or in combination with glucocorticoids or other disease-modifying
antirheumatic drugs (DMARDs). In case of failure (incomplete response,
non-response, or adverse events) on these conventional DMARDs, a biological
DMARD is started. However, a persistent ~50% of patients with an unfavourable
prognosis do not respond optimally to intensive tailored treatment during the
first three months of treatment initiation. Of patients with a milder
prognosis, minimal data is available.

The objective of this study is twofold. First, we want to investigate the
effectiveness of a COBRA-plus therapy after incomplete response on COBRA-light
therapy after 13 weeks to improve the percentage of RA-patients with a high
disease activity and/or unfavourable prognostic factors that reach a good
response to treatment. Second, we want to investigate the effectiveness of
adding prednisone to MTX monotherapy in RA-patients with initial low disease
activity failing MTX monotherapy after 13 weeks. By using treat-to-target
strategies, this study aims a high percentage of all early RA patients with a
good response to treatment at 26 weeks.

A secondary objective of this study is to study the psychometric properties of
patient reported outcomes in low disease activity and remission and investigate
the validity of the outcomes that have been shown to be important to patients
in defining remission. Another secondary objective is to study the predictive
value of both baseline and change (2 weeks) in synovial macrophage infiltration
in joints as seen on Positron Emission Tomography/Computer Tomography (PET/CT)
for clinical response to 13 weeks of COBRA-light therapy.

This is a multicenter study containing a randomisation step after incomplete
response at 13 weeks and with two strategy arms: one arm of patients with
unfavourable prognostic factors, the so-called *high risk group* (group 1), and
in the other study arm patients without unfavourable prognostic factors, the
*low risk group* (group 2). Patients are treated according to a treat-to-target
protocol, using mono- and combination therapy commonly used in clinical
practice. In case of suboptimal response after 13 weeks, patients are
randomised to continue initial therapy or intensified therapy. Treatment is
protocolised for 26 weeks and patients are followed for 52 weeks.After 26
weeks, the treating rheumatologist is at liberty to make an own treatment
decision.

At baseline, and after 4, 13, 17, 26, 39, and 52 weeks, patients will visit
their treating rheumatologist where usual measurements will take place (i.e.
number of tender and swollen joints, lab tests, x-rays of hand and feet,
patient reported outcomes in the form of questionnaires on perceived pain,
global wellbeing, and physical functioning). In addition, research
questionnaires will be collected on additional patient reported outcomes
including fatigue, sleep, stiffness, and employment. In case of a moderate or
non response according to European response criteria (EULAR criteria) after 13
weeks, treatment is randomised to continue initial therapy or to
intensification of the therapy.

At baseline, the high risk group starts with COBRA-light therapy (a combination
of MTX 25 mg per week and initially 30 mg prednisolone per day tapered to 7.5
mg prednisone per day in eight weeks). If EULAR response after 13 weeks is
good, COBRA-light therapy will be continued. If EULAR response is moderate or
none, patients will be randomised to continue COBRA-light therapy or to
intensification to COBRA-plus therapy (a combination of MTX 25 mg per week,
initially 60 mg prednisolone per day tapered to 7.5 mg prednisone per day in
seven weeks, sulfasalazine 2000 mg per day, and hydroxychloroquine 400 mg per
day).

The low risk group starts with MTX monotherapy (started with 10 mg MTX per week
increased to 25 mg per week in eight weeks). After 13 weeks, EULAR response
will be determined. If EULAR response is good, initial medication will be
continued. If EULAR response is moderate or none, patients will be randomised
to continue MTX mono-therapy or to intensification to COBRA-light therapy.

The patients participating in this cohort will receive optimalised clinical
care according to a treat-to-target strategy: in case of suboptimal response to
treatment, patients are randomised to continue initial therapy or intensified
therapy. There are no additional risks associated with participation in this
study, since all drugs are registered drugs that are already used for several
years in usual clinical practice of patient with RA (also in the combinations
defined in this study). Furthermore, rheumatologists are all very experienced
in the use of MTX, sulfasalazine, hydroxychloroquine, and glucocorticoids
(prednisolone).

Furthermore, patients have to make seven visits to the treating rheumatologist
during the first year of the study, which is one visit more than normal for
treating early RA patients. In addition, the patients will visit a research
nurse seven times a year, to monitor disease activity in a standardized way.
These visits are also routine in most Dutch rheumatological clinics in the
early phase of treatment.

Blood samples will be performed at each visit according to usual care to
measure the level of disease activity and because of safety reasons in patients
treated with MTX and prednisolone. However, per visit, up to a maximum of 52 ml
extra will be collected as stored samples for additional scientific
measurements.

Standard questionnaires will be completed at each visit. In addition, research
questionnaires will be completed, which will take approximately 30 minutes
extra per visit (week 0, 13, 26, and 52). X-rays and DXA-scans will be made at
baseline and after 26 and 52 weeks, and PET/CT-scans will be made in a part of
the patients in group 1 (*high risk group*) at baseline and after 2 weeks. For
x-rays this is one time extra compared to usual clinical practice (week 13),
DXA-scans and PET/CT-scans are not regularly performed in usual clinical
practice and are all part of research. The x-rays, DXA-scans, and PET/CT-scans
result in extra radiation exposure. Urine samples will be collected at baseline
and after 4, 13, 26, and 52 weeks.