Effect of siponimod on relevant imaging and immunological hallmarks of progressive multiple sclerosis

Prior treatment

• Negativity for varicella zoster IgG antibodies (in case of vaccination by live vaccine the beginning of therapy must be postponed of at least 30 days)
• Previous and ongoing therapies: ¿ Natalizumab (last dose less than 6 months prior to enrollment); ¿ Rituximab, Ocrelizumab (last dose less than 6-months prior to enrollment); ¿ Cyclophosphamide (last dose less than 3-months prior to enrollment)
• Previous and ongoing therapies: Fingolimod, Mitoxantrone therapy or evidence of cardiotoxicity or a cumulative dose greater than 60 mg/m2 (last dose less than 2-year prior enrollment) ¿ Alemtuzumab, cladribine, autologous stem cell transplantation and other immunosuppressive treatments with expected effect of over 6 months (any time) ¿ Intravenous corticosteroid cycle to treat MS clinical relapse (1-month before enrollment)

Other illness

• History of hypersensitivity to any metabolites or drugs of the same class as siponimod
• Hypersensitivity to the active substance or to peanuts, soy or to any of the excipients
• Immunodeficiency syndrome
• History of progressive multifocal leukoencephalopathy or cryptococcal meningitis
• Rheumatic disease under specific treatment (including chronic use of steroid)
• Severe active infections (regard to positive result to HBV, HCV, HIV, Quantiferon)
• Myocardial infarction, unstable angina, stroke (any time), TIA (in the last 6 months) • NYHA Class III or IV heart failure

Lab values

• First- or second-degree [Mobitz type I] AV block, • Second grade AV block (Mobitz type II); • Third grade AV block (unless patient has a functioning pacemaker) • Sinus bradycardia (HR < 55 bpm) or symptomatic bradycardia (i.e. history of recurrent syncope) • QTc =500 msec
• Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN)
• Previous and ongoing therapies: Antiarrhythmics Class Ia (e.g. quinidine, procainamide), Class III (amiodarone, sotalolo) drugs and those that may decrease heart rate (e.g. beta-blockers, calcium channel blockers, ivabradine and digoxin)
• Hematologic alterations (lymphocyte count not within normal limits)

Other

• Patients homozygous for the CYP2C9 *3 *3 allele
• Pregnancy or breast feeding. • Fertile women who do not use effective methods of contraception.
• Active malignities
• Complete left bundle branch block

• Age 18-65 years
• Active progressive MS course after an initial relapse clinical course defined as an EDSS progression of at least 1 point with a history of relapse and/or evidence of radiological activity defined as new/enlarging T2-FLAIR hyperintense or Gd-enhancing or paramagnetic rim positive lesion on MRI acquired, in the 2 years before the enrolment
• Availability of a 3T MRI performed within the last 2 years. This MRI must include these sequences: - 3D T1 weighted Fast Field Echo (FFE) - 3D Fluid Attenuated Inversion Recovery (FLAIR) - 3D Echo Planar Imaging Susceptibility weighted (Magnitude and Phase)
• Availability of a detailed clinical data on medical history with neurological evaluation performed at least twice in the past two years (or once in the past year)
• EDSS between 3.0 and 6.0
• Less than 5 years since entering the progressive phase of the disease
• Female subjects must not be pregnant or breast feeding at T0 nor during the study phase