The safety and cost-effectiveness of discontinuing disease-modifying therapies in stable relapsing-onset multiple sclerosis (DOT-MS): a randomized rater-blinded multicenter trial.

The past few years, several new effective drugs have come onto the market for
the treatment of relapsing remitting MS (RRMS), all of which have potentially
serious side effects. The arrival of these drugs has led to a new aim for
treating MS patients: achieving a status of complete clinical and radiological
control of inflammatory events. With these adjusted goals, medication is often
started at an earlier stage and the disease is treated more aggressively. This
leads to better control of the disease, but also to increased exposure to
possible (serious) side effects. A considerable group of patients with a fully
stable-disease under treatment merely have a benign or less inflammatory
disease course rather than a necessity for treatment to prevent inflammation.
This raises the question whether and when patients who have been stable under
medication for years can safely discontinue the treatment. The hypothesis of
this study is that discontinuing medication after >5 years without evidence of
inflammatory disease activity does not result in return of inflammatory disease
activity.

The aim of this study is to identify whether it is possible to safely
discontinue treatment in stable RRMS patients who have shown no evidence of
active inflammation in the years prior to inclusion in terms of the return of
inflammatory disease activity clinically and/or radiologically.


Primary research question:
- Can we safely discontinue first-line medication in long-term stable RRMS
patients without the return of inflammatory disease activity clinically and
radiologically?

Secondary research questions:
- Does the discontinuation of first-line treatment have an effect on disability
progression?
- Does the discontinuation of first-line treatment improve the quality of life
for the patient?
- What is the effect of discontinuation of first-line treatment on individual
MRI outcome measures such as number of lesions and atrophy measurements?
- Is it possible to predict possible return of inflammatory activity with
biomarkers such as neurofilament light (NFL) or patient characteristics such as
disease activity prior to DMT?
- In case of emerging disease activity after cessation of DMT, will a restart
of DMT result in NEDA again and if so, how long does it take?
- In case of emerging disease activity after treatment cessation, are there any
differences between the different DMT compounds?
- Is discontinuation of first-line DMT associated with OCT measurements and eye
movement measurements?
- Is it possible to detect and predict (return of) inflammatory disease
activity and disease progression with digital biomarkers using mobile
applications such as MS sherpa and Neurokeys?

Multi-center randomized and controlled, rater-blinded trial in the Netherlands.
130 patients with RRMS will be assigned to either discontinue the previously
used disease modifying therapy (DMT) or to continue their DMT. Patients will be
followed for 2 years, with the possibility to participate in an extension phase
of the trial of 2 years.

The intervention is the discontinuation of previously used disease-modifying
therapy (DMT).

Patients in the continuation group and patients in the discontinuation group
will be evaluated at baseline, after 3, 6, 12, 18 and 24 months. Evaluation
consists of clinical examination (EDSS and MSFC), radiological evaluation
(MRI), questionnaires and serum samples. For patients in the Amsterdam UMC,
OCT/Eyetracker measurements will be done at baseline, 3, 12 and 24 months.
Current standard of care for MS-patients that use DMT's consists of a mininum
evaluation frequency of once a year, mostly including MRI-scans. This means
that patients in our study will be evaluated more frequently and more
extensively than patients who receive standard clinical care. In addition, two
mobile applications can be installed on the patients' smartphone (MS sherpa and
Neurokeys). The MS sherpa application asks patients two complete three short
tasks every two weeks, which take approximately 5 minutes to complete.
Neurokeys replaces the patients' standard keyboard and collects data on the
background during regular use of the smartphone.

The main risk of the intervention is return of inflammatory disease activity
after discontinuing DMT. We will build in a safety-strategy (go-no-go strategy)
to control for emerging disease activity (and patients safety). Interim
analyses will be done after inclusion of the 40th, 70th and 100th patient. In
both the continuation and discontinuation group, the proportion of patients
that showed return of inflammatory disease activity - defined as an objectified
MS relapse or 3 or more lesions on T2-weighted MRI-images or 2 or more
gadolinium enhancing lesions on T1-weighted post-contrast MRI suggestive of
demyelination - will be counted and compared between the treatment arms.

If there are more patients with return of inflammatory disease activity
(according to the above mentioned definition) in the discontinuation group than
in the continuation group, and the 95% confidence interval of the difference in
the proportion of patients with return of disease activity between both groups
does not include 0, we will discuss premature ending of the study with the
DSMB.

For optimal safety the DSMB will monitor the decision making on premature
termination every 3 months. The DSMB may advice to terminate the trial
prematurely if disease activity exceeds above mentioned thresholds.