Chronotherapy in Inflammatory Arthritis (ChronIA trial): a randomized controlled trial comparing the effectiveness of morning and evening dosing of tofacitinib extended-release

Circadian rhythms control, under activity of biological clock genes, several
daily processes which can be observed in our physiology and behaviour (i.e.
secretion of hormones and cytokines and sleeping and eating). Disruption of the
circadian rhythm may lead to immune dysregulation. For example, shift workers
have a higher chance at developing rheumatoid arthritis (RA). In line with
this, various inflammatory arthritis symptoms show a distinctive diurnal
pattern, including pain and joint stiffness. However, in daily practice we
often do not take advantage of these circadian rhythms, especially not with
regard to treatment, also known as chronotherapy.

Perry et al previous showed that pro-inflammatory cytokines, i.e. tumour
necrosis factor (TNF) and interleukin(IL)-6, levels are higher at night-time
compared to healthy controls and that especially IL-6 an overnight variation
had, which was also correlated with the severity of morning stiffness. This
altered daily variation of pro-inflammatory cytokines is provoked by a
desynchronization of the circadian rhythm, which is caused by an altered
expression of circadian clock genes. Moreover, this desynchronization of the
circadian rhythm may lead to dysbiosis, but one can also reason vice versa.
Kaneshiro et al recently demonstrated that biologicals modulate the expression
of circadian clock genes in a positive manner, which might also lead to
rebuilding microbiota. Subsequently, a balanced microbiota, or eubiosis, might
lead to relief of symptoms.

Although aforementioned reasoning makes it plausible that the timing of
treatment in inflammatory arthritis might improve the efficacy of the given
drug, there are only a handful of trials that investigate this concept. In the
past chronotherapy using NSAIDs, glucocorticoids and methotrexate was
investigated, which showed a significant improvement in symptoms, including
functional ability, morning stiffness and disease activity, but also a
reduction in dosage without loss of efficacy. To our knowledge, studies looking
into chronotherapy using biologicals and/or JAK inhibitors in inflammatory
arthritis patients are non-existing, but there are a few studies in mice with
collagen-induced arthritis. Yaekura et al, for example, showed that evening
dosing of baricitinib enhances the efficacy.

Lastly, we want to emphasize that most clinical research in inflammatory
arthritis on circadian rhythms and chronotherapy is exclusively done in
rheumatoid arthritis.

Therefore, the aim of this project is to compare the effectiveness of
tofacitinib extended release chronotherapy, morning versus evening dosing, in
inflammatory arthritis, rheumatoid arthritis and psoriatic arthritis, patients
from a patient*s, clinical as well as a translational point of view.

This study has been transitioned to CTIS with ID 2024-517865-17-00 check the CTIS register for the current data.

We hypothesize that the timing of treatment in IA, also known as chronotherapy,
matters and that the efficacy of tofacitinib XR depends on it.Therefore, the
aims of this randomized controlled trial are:
1. To compare the clinical effectiveness of tofacitinib extended release (XR)
chronotherapy for inflammatory arthritis by looking at the difference in the
Routine Assessment of Patient Index Data 3 (RAPID-3) between morning and
evening dosing of tofacitinib XR after 3 months of treatment. (primary outcome)
2. To evaluate if sleep quality and morning stiffness severity differs between
morning and evening dosing of tofacitinib XR.
3. To compare patient-relevant outcome (PRO) domains; namely pain, fatigue,
activity limitation, quality of life and worker productivity between both
administration times.
4. To explore if the expression of circadian clock genes change over time and
whether these changes correlate with treatment response.
5. To investigate whether treatment with Tofacitinib XR leads to restoration of
eubiosis.
6. To explore whether aforementioned effects differ between rheumatoid
arthritis and psoriatic arthritis patients and/or deteriorate or improve after
switching from administration time.

The Chronotherapy in Inflammatory Arthritis (ChronIA) trial is an open-label,
randomized controlled trial, which will be carried out in the Erasmus Medical
Center and IJsselland Hospital. Patients will be randomized using minimization
randomization stratified for diagnosis, by an independent call center. Trained
research nurses will examine patients and calculate the DAS or DAPSA depending
on the diagnosis.

Patients are randomized into morning or evening dosing of tofacitinib XR (11mg
q.d.) for 3 months, which is followed by switching to the alternate regimen for
the next 3 months. Patients will be instructed to take the tofacitinib XR at
approximately 08:00 - 09:00 and 22:00 - 23:00 hours.

Concomitant treatment with csDMARD(s) and prednisone (or equivalent) at a dose
<=7.5mg is allowed, but participants have to have been receiving a stable dose
for >=8 weeks prior to randomization and this will be continued during the
entire follow-up. It is, therefore, not allowed to change the csDMARD and/or
glucocorticoid dosage, including the time of administration.

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 in accordance with the protocol if (serious) adverse
events, using WHO*s adverse reaction terminology, are seen by the attending
rheumatologist.

Patients will be assessed at baseline and after 1, 3 and 6 months of treatment.
At each visit patients will fill out online questionnaires and are seen by the
research nurse, who calculates the DAS or DAPSA depending on the diagnosis.
Additional blood and faecal samples will be taken at baseline (T0), 1 month
(T1; only blood), 3 months (T3) and 6 months (T6). Finally, patients will wear
an actigraph unit, a wristwatch-like package, on the wrist 2-times for 2 weeks
at home. The actigraph will be picked up by the patient in the hospital 2 weeks
prior to the visit.

See section study design

If successful, this study will define the optimal dosing time of tofacitinib XR
and could be a step towards the implementation of chronotherapy on a regular
basis in daily practice. Moreover, it may also help better address well-known
problems such as morning stiffness and fatigue, which often persist after
reaching low disease activity.

The prescribed medication, Tofacitinib XR, within this trail is approved and
used according to label. Generic ('off the shelf') commercial supplies are to
be used for Tofacitinib XR. Moreover, the medication protocol within this trial
complies with current (inter)national guidelines. Nevertheless, safety
monitoring will be carried out according to Dutch guidelines, and includes
laboratory tests at fixed intervals.

Furthermore, study visits are planned as much as possible on the same day as
the outpatient clinic visit. Questionnaires can be filled out online at home.
The actigraph unit, a wristwatch-like package, is worn on the wrist 2-times for
2 weeks at home, but does need to be picked up at the hospital. Blood samples
are taken after the study visit and we will try to combine them with the
routine blood tests. Faecal samples are collected and stored at home 24 hours
prior to the visit and are brought in by the patient. 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, wearing
the actigraph and additional blood and faecal samples).