PeRsonalIzed MEdicine in Rheumatoid Arthritis (PRIMERA trial): a multicenter, single-blinded, randomized controlled trial comparing usual care with a tailor-made approach

Clinical and radiographic outcomes in RA have improved enormously due to early
detection of the disease, early initiation of *intensive* therapy and a
treat-to-target approach. The emphasis on early diagnosis and treatment has led
to the development of the 2010 ACR/EULAR classification criteria for RA. With
the introduction of these new classification criteria, the heterogeneity of the
RA disease spectrum has become more visible.
Despite the heterogeneity of RA current management recommendations still adopt
an *one-size-fits-all* approach, where ideally individualized treatment, or
personalized medicine, is preferred. The prerequisite for precision medicine
is the ability to classify individuals into subpopulations that differ in their
response to a specific treatment, which for RA still needs to be unraveled.
However, we do believe that it is nowadays possible to individualize RA
management by taking into account the presence of autoantibodies and the quick
response to glucocorticoids and targeted synthetic (ts)DMARDs.

First, the presence of autoantibodies, anti-citrullinated protein antibody
and/or rheumatoid factor, is associated with a worse prognosis. Even current
treatment recommendations advise to consider more aggressive therapy for RA
patients with autoantibodies compared to RA patients without autoantibodies,
also known as seronegative RA, when they fail on their conventional synthetic
(cs)DMARD strategy. Moreover, literature suggests that these different disease
subsets could be treated differently, with less intensive treatment regimens
for seronegative RA patients. Recently, we demonstrated that seronegative RA
patients can be treated with hydroxychloroquine with similar efficacy to
methotrexate (MTX).

Secondly, delayed treatment responses increase the risk of erosive disease and
functional impairment and also significantly influences the quality of life for
RA patients. However, the optimal effect of csDMARDs is at least 6-12 weeks,
which implies that the right choice of the initial csDMARD strategy has an
important role in how fast treatment goals are attained. We previously showed
that treatment goals are attained faster with a combination of csDMARDs
compared to MTX monotherapy. However, treating physicians try to avoid problems
as over-treatment and accompanying (serious) adverse events. Therefore, it
would be helpful to be able to predict the initial treatment response as early
as possible, with the purpose that rheumatologist can initiate less aggressive
treatment and intensify it without delay when necessary. The early
glucocorticoid response, measured within 1 month, is a useful tool for
recognising RA patients who will probably fail on their initial csDMARD
strategy and is, therefore, the key for aforementioned approach.

Finally, if the treatment target is not achieved with csDMARD(s) a biological
(b-) or tsDMARD should be added. In daily practice TNFinhibitors are often the
first choice, because of experience, long-term safety data and costs. However,
the time to maximum response is longer for TNF inhibitors compared to the
recently available tsDMARDs. To illustrate, the time to maximum ACR50 response
is 8 weeks for filgotinib, compared to 24 weeks for adalimumab, the most
prescribed TNF inhibitor. If we apply same reasoning as previous paragraph, an
early inadequate tsDMARD response, measured within 8 weeks, is an indication to
switch to a bDMARD.

Although our elucidate tailor-made management approach is based upon 3
substantiated concepts, they have never been combined to one approach. Nor has
it shown its benefit over routine care. Therefore, the aim of this project is
to compare the effectiveness of our tailor-made management approach with
routine care from a clinical, patient*s as well as an economic point of view.In
addition we will investigate if our tailor-made management approach can be
improved by adding biomarkers.

This study has been transitioned to CTIS with ID 2024-511530-12-01 check the CTIS register for the current data.

We hypothesize that treatment of RA can be individualized by taking into
account the presence of autoantibodies and quick response to glucocorticoids
and JAK inhibitors. Therefore, the aims of this randomized controlled trial
are:

1. To compare clinical effectiveness between our tailor-made management
approach and routine care in newly diagnosed, DMARD naive, rheumatoid arthritis
patients, by looking at:
a. Proportion of patients using a biological or targeted synthetic DMARD after
9 months of treatment.
b. Disease Activity Score (DAS) over time
Noteworthy is the fact that our tailor-made management approach is only
superior to routine care if treatment goals are attained faster without the use
of more biological or targeted synthetic DMARDs.

2. To evaluate the cost-effectiveness of our tailor-made treatment approach
versus routine care, by using the incremental cost-effectiveness ratio (ICER)
as outcome, which is the ratio of the difference in costs to incremental
benefits between both management approaches.

3. To evaluate if patient satisfaction, compliance and patient participation is
increased with our tailor-made management approach compared to routine care

4. To explore whether our tailor-made management approach can be more
individualized by adding biomarker(s).

The PeRsonalIzed MEdicine in RA (PRIMERA) trial is a multicenter,
single-blinded randomized controlled trial, which will be carried out in
multiple hospitals in the southwestern part of the Netherlands. Patients will
be randomized using minimisation randomization stratified for center, by an
independant call center. Trained research nurses, blinded to the allocated
treatment arm throughout the study, will examine patients and calculate the
Disease Activity Score (DAS).

Patients are randomized into routine care or our tailor-made approach. In
routine care patients are initially treated with methotrexate (MTX) and
glucocorticoids (GCs) once intramuscularly (im). The initial therapy of
patients randomized to our tailor-made approach depends on the presence of
autoantibodies. Patients without auto-antibodies will receive
hydroxychloroquine (HCQ) + GCs im, while patients with auto-antibodies start
with
MTX + GCs im.

Both management approaches use a treat-to-target strategy, aiming for low
disease activity (DAS<2.4). If DAS>=2.4 treatment is intensified until the
aforementioned target is reached. In routine care medication can be intensified
every 3 months, reflecting current daily practice. The intensifications steps
are in following order: (1) Triple DMARD therapy (TDT), consisting of MTX,
sulfasalazine (SASP) and HCQ; (2) MTX + Filgotinib (FIL); (3) MTX + TNF
inhibitor (TNFi); and (4) MTX + 2nd TNFi. In our tailor-made approach besides
the possible 3 monthly treatment intensification, medication alterations can
also occur after 1 month and 4 months, depending on the response to
respectively GCs im and filgotinib (FIL). A good response to GCs im and FIL
after respectively 1 and 4 months is defined as a DAS<2.4 OR ΔDAS>0.6. The
intensifications steps in the tailor-made management approach are the same as
routine care.

DMARD dosages are MTX 25 mg/week orally (week 1 15mg/week; week 2 20mg/week and
week 3 and thereafter 25mg/week), SASP 2 g/day (week 1 500mg bid; week 2 500mg
tid; and week 3 and thereafter 1000mg bid) and HCQ 400 mg/day. GCs are given
once intramuscularly with either methylprednisolone 120mg or triamcinolone
acetonide 80mg. Filgotinib is a once-daily oral therapy of 200mg. The TNFi,
including adalimumab 40mg/2 weeks s.c; etanercept 50mg/week s.c; certolizumab
pegol 200mg/2 weeks s.c (after loading doses of 400mg/2 weeks at week 0, 2 and
4).; golimumab 50mg/4 weeks s.c.; and infliximab 3-5mg/kg at week 0, 2 and 6
and 8 weekly thereafter, is free of choice for the treating rheumatologist.
Concurrent treatment with NSAIDs and intra-articular GC injections (maximum of
2 per 3 months) will be allowed during follow-up.

The prescribed medication within this trail are all approved and used according
to label. Nevertheless, safety monitoring will be carried out according to
Dutch guidelines, and includes laboratory tests at fixed intervals. The study
drug will be stopped or the dosage lowered in accordance with the protocol if
(serious) adverse events, using WHO*s adverse reaction terminology, are seen by
the attending rheumatologist. MTX can be given subcutaneously if patients
experience gastrointestinal complaints. If MTX is stopped for safety reasons,
it will be substituted by leflunomide (20mg/day).

Patients will be assessed every 3 months with additional visits at months 1,2
and 4. At each visit patients will fill out online questionnaires and are seen
by the research nurse, who calculates the DAS. Additional blood samples will be
taken at baseline (T0), 1 (T1) and 3 (T3) months and only at 2 (T2), and 4
(T4) months if DAS>=2.4 at the previous visit.

See section study design.

If successful, this study will define a more tailor-made management approach
for RA and could be a step towards personalized medicine. Problems as
over-treatment and accompanying (serious) adverse events are then circumvented
by this tailor-made management approach, while disease control is attained even
faster without the use of more b- or tsDMARDs.
Within this trial all prescribed drugs are used according to label.
Furthermore, study visits are planned as much as possible on the same day as
the outpatient clinic visit and questionnaires can be filled out online at
home. Blood samples are taken after the study visit and we will try to combine
them with the routine blood tests. Therefore, in our opinion, the knowledge we
are expecting to gain from this study outweigh the study burden (number of
study visits, time for filling out online questionnaires and additional blood
samples).