Siponimod fumaric acid for Secondary progressive multiple sclerosis|Progressive multiple sclerosis

Inclusion criteria

• {"criterion_text":"- Age 18-65 years"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- EDSS between 3.0 and 6.0"}
• {"criterion_text":"- Less than 5 years since entering the progressive phase of the disease"}
• {"criterion_text":"- Female subjects must not be pregnant or breast feeding at T0 nor during the study phase"}

Exclusion criteria

• {"criterion_text":"- Patients homozygous for the CYP2C9 *3 *3 allele"}
• {"criterion_text":"- Immunodeficiency syndrome"}
• {"criterion_text":"- History of progressive multifocal leukoencephalopathy or cryptococcal meningitis"}
• {"criterion_text":"- Hematologic alterations (lymphocyte count not within normal limits)"}
• {"criterion_text":"- Rheumatic disease under specific treatment (including chronic use of steroid)"}
• {"criterion_text":"- Severe active infections (regard to positive result to HBV, HCV, HIV, Quantiferon)"}
• {"criterion_text":"- Active malignities"}
• {"criterion_text":"- Myocardial infarction, unstable angina, stroke (any time), TIA (in the last 6 months) • NYHA Class III or IV heart failure"}
• {"criterion_text":"- Complete left bundle branch block"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- History of hypersensitivity to any metabolites or drugs of the same class as siponimod"}
• {"criterion_text":"- Hypersensitivity to the active substance or to peanuts, soy or to any of the excipients"}
• {"criterion_text":"- Pregnancy or breast feeding. • Fertile women who do not use effective methods of contraception."}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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)"}

Primary endpoints

• {"endpoint_text":"- The study endpoint is the change (assumed to be a reduction) of the susceptibility of the rim lesions after treatment with siponimod in comparison to the “natural” change of this parameter during a recent period-time preceding treatment (no later than two years before) with siponimod, so that for each patient an internal comparison will be available.","definition_or_measurement_approach":"Change in susceptibility of paramagnetic rim lesions measured by MRI after treatment with siponimod compared with the patient's own recent pre-treatment imaging (internal retrospective comparison using MRI no later than two years before enrolment)."}

Secondary endpoints

• {"endpoint_text":"- To evaluate the effect of siponimod in reducing the number of SEL comparing to the period prior the treatment (retrospective phase) with the study phase (T3 vs T12 and T3 vs T24).","definition_or_measurement_approach":"Comparison of number of SEL (slowly expanding lesions) between retrospective pre-treatment period and study phase at timepoints (T3 vs T12 and T3 vs T24)."}
• {"endpoint_text":"- To describe the individual changes in CSF levels of specific makers of activated microglia/macrophages (sCD14, sCD163, TNF, sTNFR1, sTNFR2, Chitinase 3-1like) and of neuronal/axonal damage (neurofilament-light chains, parvalbumin) from baseline to T24","definition_or_measurement_approach":"Measurement of listed CSF biomarkers at baseline and at T24 to describe individual changes."}
• {"endpoint_text":"- To evaluate the changes of sCD14, sCD163, TNF, sTNFR1, sTNFR2, Chitinase 3-1like, neurofilament-light chains, and parvalbumin in serum of patients at baseline and at T6, T12, T18, T24","definition_or_measurement_approach":"Serial serum biomarker measurements at baseline, T6, T12, T18 and T24 to evaluate changes over time."}
• {"endpoint_text":"- To evaluate the EDSS change between the retrospective phase and the study phase (T0 vs T12 and T12 vs T24","definition_or_measurement_approach":"Comparison of Expanded Disability Status Scale (EDSS) scores between retrospective phase and study phase at indicated timepoints (T0 vs T12 and T12 vs T24)."}
• {"endpoint_text":"- To evaluate changes in cognitive functioning during the two-year study phase (T0-T24)","definition_or_measurement_approach":"Assessment of cognitive function over the study phase from T0 to T24 (specific cognitive measures not detailed in the CTIS record)."}
• {"endpoint_text":"- Treatment emergent adverse effect (TEAE) and serious adverse event (SAE) at each follow-up visit","definition_or_measurement_approach":"Collection and reporting of TEAEs and SAEs at each follow-up visit."}

Italy

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

05-11-2024

Processing Time Days

43

Number Of Sites

2

Number Of Participants

60

Primary sponsor

Full Name

Azienda Ospedaliera Universitaria Integrata Verona

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy

Third parties

• {"country":"","full_name":"Novartis Farma Spa","duties_or_roles":"Monetary support (sourceOfMonetarySupport listed in CTIS record)","organisation_type":""}