A Randomized Open Label Trial Exploring the Soluble and Imaging Biomarker Dynamic Responses to Tolebrutinib Compared to Rituximab Treatment in Patients with Multiple Sclerosis (MS)

Prior treatment

• Current diagnosis of primary progressive MS (PPMS). 2. Relapse within 12 months prior to screening and/or gadolinium-enhancing lesion at screening MRI.
• Any history of active cancer within 5 years prior screening.
• Relapse within 12 months prior to screening and/or gadolinium-enhancing lesion at screening MRI
• Clinically significant acute neurological events including traumatic brain injury in the 12 months prior to screening
• Usage of any of the following medications prior to the Screening visit: a. Any usage of interferon beta, glatiramer acetate, IV immunoglobulin (IVIG), dimethyl fumarate or teriflunomide within 24 months prior to Screening. b. Any history of exposure to mitoxantrone, cladribine, alemtuzumab, cyclophosphamide, systemic cytotoxic therapy, total lymphoid irradiation, and/or bone marrow transplantation at any time. c. Any usage of natalizumab within 24 months prior to Screening. d. Any usage of highly potent immune modulating therapy, such as: ocrelizumab, ofatumumab, fingolimod, siponimod, ozanimod or anticytokine therapy, plasmapheresis or azathioprine within 24 months prior to Screening. e. Any usage of any experimental treatment if not washed out for ≥5 half-lives or ≥24 months (whichever is longer), except rituximab which is allowed before the study. f. Any usage of BTK inhibitors.
• Is receiving potent and moderate inducers and inhibitors of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes
• Is receiving any anticoagulant/antiplatelet therapies.
• Has a history or presence of significant other concomitant illness that, according to the PI or treating physician’s judgment, would adversely affect participation in this study; examples include but are not limited to clinically significant cardiovascular, renal, hepatic, or metabolic disease, as well as any unstable medical condition as determined by the investigator.

Other illness

• Any major medical or psychiatric disorder that would affect the capacity of the patient to fulfill the requirements of the study.
• History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (NYHA class 3 or 4), and/or presence of ECG findings at Screening deemed as clinically significant by the Investigator.
• History of, or positive serology for viral hepatitis B not explained by vaccination.
• History of, or positive serology for viral hepatitis C or human immunodeficiency virus (HIV) at any time
• Any disease other than MS (e.g. myelitis and /or bilateral optic neuritis) that could better explain the patient's signs and symptoms.

Lab values

• Any history of a bleeding disorder or known platelet dysfunction at any time prior to the first screening visit, and/or platelet count less than 150,000/μL at the screening visit.
• Any history of clinically significant liver disease, and/or presence of abnormal liver function tests: AST or ALT > 1.5 times upper limit of normal range (ULN), or conjugated bilirubin > 1.5 times ULN (unless due to Gilbert syndrome or non-liver-related disorder), or AP > 2 times ULN (unless caused by non-liver related disorder or explained by a stable chronic liver disorder) or GGT > 3 times ULN.

Other

• Pregnant or breastfeeding women.
• Known inability to undergo an MRI scan.
• Inability to follow study instructions, or complete study assessments, as defined by the protocol.
• Legal incapacity or limited legal capacity.
• Positive pregnancy test at screening.
• CTCAE Grade 2 or greater lymphopenia.

• The subject has given written informed consent to participate in the study.
• Be willing and able to follow all study procedures and assessments according to the study protocol.
• Female patients of childbearing potential (FPCBP) or procreative male patients (PMP), willing to use highly effective contraceptive methods throughout the study duration and at least until 5 months after the last study treatment.
• Current diagnosis of MS, based on McDonald 2017 criteria.
• Having received treatment with rituximab, as per local clinical routine for at least 24 months prior to the Screening Visit, with latest dose administered between 3 and 9 months prior Screening Visit.
• Having expanded disability status scale (EDSS) 2 -6 inclusive at Screening.
• Present clinical worsening in one or more neurological domains as assessed by EDSS, ambulatory function as assessed by 6MWT or T25FW, cognitive functioning as assessed by SDMT or increased need of walking aids or pharmacological/procedures for bowel and bladder functions, MRI (atrophy), PROs, work and lifestyle, clinical judgement over the last year.
• At least 18 years old
• No disease modifying therapies (DMTs) other than rituximab, within 24 months of Screening
• No contraindication to Biomarker assessments: MRI, blood/serum collection and CSF collection.
• Agreeing to undergo a maximum of three lumbar punctures.