A randomized, double-blind, double-dummy, parallel-group study, comparing the efficacy and safety of remibrutinib versus teriflunomide in participants with relapsing multiple sclerosis, followed by extended treatment with open-label remibrutinib.

Multiple Sclerosis is a chronic disorder affecting the central nervous system.
Inflammations occur in the nerve tissue which results in the transmission of
information in the central nervous system being impaired and nerves dying off.
As a result, over time the patient suffers from increasingly severe physical
complaints, leading to serious limitations. It is therefore important to start
an effective treatment at an early stage in order to prevent permanent damage.
Currently, the MS treatment options of the neurologist consists of medication
(DMTs) that target the T-cells or medication that targets the B-cells. The DMTs
differ in mechanism of action, efficacy, safety profile, method of
administration and ease of use. B-cells have an essential function mainly in
the early phase of an immune response by regulating T-cells and inflammation
through the production of cytokines. B-cells are present in the inflammatory
foci of the nervous system and in the cerebrospinal fluid of patients with MS.
Recent anti-CD20 monoclonal antibodies cause depletion of B cells and have
proven efficacy and safety in the treatment of MS. These agents are
administered intravenously or subcutaneously (in a hospital setting or at home)
and are increasingly seen as one of the most effective treatment options in MS.
However, despite the major therapeutic advances made with the introduction of
B-cell depleting monoclonal antibodies, further improvements for patients need
to be considered. In particular, options that effectively impede B cell
functions relevant to MS but without depleting all B cells would allow rapid
immune recovery and avoid potential risks of chronic B cell depletion. In
addition, an oral route of administration increases convenience and is
preferred by many MS patients over parenteral forms of administration.
Inhibition of Bruton*s tyrosine kinase (BTK) is considered a viable approach to
modify disease in RMS, since BTK is involved in B-cell activation and antigen
presentation, as well as in the activation of myeloid cells, all to be believed
to be potentially relevant in RMS pathogenesis.
Remibrutinib is a selective, potent, covalent inhibitor of BTK in B-cells and
myeloid cells, hence, based on the known pharmacology and mode of action,
remibrutinib is expected to exert beneficial clinical effects in a variety of
autoimmune and chronic inflammatory diseases (including RMS) driven by
immunological mechanisms involving B-cells, macrophages or mast cells, as well
as pathologic self- and non-self-antibodies of the IgG type.
Bruton's tyrosine kinase inhibitors (BTKi) (similar to remibrutinib),
demonstrated potent anti-inflammatory effects in reducing the cumulative number
of Gd-enhancing lesions on MRI, and demonstrated anti-inflammatory MRI effects
of BTKi in RMS.
Remibrutinib has a favorable pharmacological profile in terms of potency,
selectivity for BTK and safety (as observed in available Phase II data) in
different indications at relevant doses and may offer a novel therapeutic
option for participants with RMS.

This study has been transitioned to CTIS with ID 2023-509345-12-00 check the CTIS register for the current data.

The purpose of the study is to provide efficacy, safety and tolerability data
for remibrutinib to support regulatory approval worldwide as a treatment for
relapsing multiple sclerosis (RMS). Two identical Phase III trials
(CLOU064C12301 and CLOU064C12302) will be conducted simultaneously.

This study consists of an initial Core Part (CP) (maximum duration per
participant of up to 30 months), followed by an Extension Part (of up to 5
years duration) for eligible participants.
The Core Part is a randomized, double-blind, double-dummy, active
comparator-controlled, fixed-dose, parallel-group, multi-center study in
approximately 800 participants with RMS. The treatment duration of the Core
Part for individual participants will be variable based on when the Core Part
End of Study (EOS) criteria are met. The maximal duration of the Core Part for
an individual participant will be 30 months (~2.5 years).
The Extension Part is an open-label, single-arm, fixed-dose design in which
eligible participants are treated with remibrutinib for up to 5 years.
A second identical study (LOU064C12302) will be conducted simultaneously.
Two studies are being conducted to meet the regulatory requirement of
demonstrating reproducible results. The reason for conducting identical studies
(same patient population and comparator) is to allow for pooling of the data
from two studies to generate sufficient power to assess the impact on
disability progression (key secondary objective).

For initial Core Part of the study
* Remibrutinib 100 mg/ matching placebo Tablet 100 mg b.i.d. oral use (blinded)
* Teriflunomide 14 mg/ matching placebo Capsule 14 mg q.d. oral use (blinded)
Remibrutinib 100 mg Tablet 100 mg b.i.d. oral use open-label (during EP)

Risks: side-effects of the study medication and procedures (see E9)
Burden: amount of visits and examinations/procedures per visit (see E4)