Siponimod for Secondary progressive multiple sclerosis | Progressive multiple sclerosis

Inclusion criteria

• {"criterion_text":"- Age 18-65 years\n- 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 lesion on MRI acquired, in the previous 2 years before the enrolment\n- 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\n- Availability of detailed clinical data on medical history with neurological evaluation performed at least twice in the past two years (or once in the past year)\n- EDSS between 3.0 and 6.0\n- Less than 5 years since entering the progressive phase of the disease\n- Female subjects must not be pregnant or breastfeeding at T0 nor during the study phase. Before enrollment, female subjects of childbearing potential must be informed about risks to the fetus, must have a negative pregnancy test and must use highly effective methods of contraception to prevent pregnancy during treatment as well as for at least 10 days after stopping treatment. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: a) combined (estrogen and progestin containing) hormonal contraception associated with inhibition of ovulation: i) oral ii) intravaginal iii) transdermal b) progestogen-only hormonal contraception associated with inhibition of ovulation: i) oral ii) injectable iii) implantable c) intrauterine device (IUD) d) intrauterine hormone-releasing system (IUS) e) bilateral tubal occlusion f) vasectomised partner g) sexual abstinence Male subjects must use a condom if their partners are fertile, and the female partner must use a highly effective contraception measure, according to the document “Recommendations related to contraception and pregnancy testing in clinical trials, Version 1.1” (CTFG 21/09/2020"}

Exclusion criteria

• {"criterion_text":"- Patients homozygous for the CYP2C9 *3 *3 allele\n- 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)\n- 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\n- Abnormal skin or ophthalmic examination\n- Diabetes mellitus\n- Pregnancy positive test or breastfeeding\n- Fertile women who do not use highly effective methods of contraception\n- Immunodeficiency syndrome\n- History of progressive multifocal leukoencephalopathy or cryptococcal meningitis\n- Hematologic alterations (lymphocyte count or platelets not within normal limits)\n- Rheumatic disease under specific treatment (including chronic use of steroid)\n- Severe active infections (regard to positive result to HBV, HCV, HIV, Quantiferon)\n- Active malignities\n- Myocardial infarction, unstable angina, stroke (any time), TIA (in the last 6 months) ¿ NYHA Class III or IV heart failure ¿ Complete left bundle branch block ¿ 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\n- Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN) or kidney dysfunction (serum creatinine not within normal limits dysfunction"}

Primary endpoints

• {"endpoint_text":"- To characterize the effect of the drug on cerebrospinal fluid markers of chronic intrathecal inflammation. According to literature, to our previous studies and preliminary data, that pointed to a key role of CXCL13 in mediating B-cell accumulation and its association with disease severity and progression, the sample size has been calculated taking in account as primary endpoint to measure changes in the CSF levels of CXCL13.","definition_or_measurement_approach":"Change in CSF levels of CXCL13 measured in cerebrospinal fluid (CSF) samples; primary endpoint is measurement of changes in CSF CXCL13."}

Secondary endpoints

• {"endpoint_text":"- the characterization of intrathecal (and paired blood) adaptive and immune cell subsets through a high-dimensional flow cytometry performed at T0 and after two years of treatment (T24)","definition_or_measurement_approach":"High-dimensional flow cytometry of intrathecal and paired blood adaptive and immune cell subsets at baseline (T0) and at 24 months (T24)."}
• {"endpoint_text":"- Evaluation of paired blood and CSF markers of inflammation and neurodegeneration at T0 and T24","definition_or_measurement_approach":"Measurement of specified blood and CSF biomarkers of inflammation and neurodegeneration at T0 and T24."}
• {"endpoint_text":"- Assessment of CSF oligoclonal bands status and number at T0 and after two years of treatment (T24)","definition_or_measurement_approach":"Assessment of CSF oligoclonal band status and count at baseline and at 24 months."}
• {"endpoint_text":"- Assessment of the main pro-inflammatory (e.g., prostaglandins and leukotriens) and pro-resolving (e.g., resolvins, protectins, maresins and lipoxins) lipids at T0 and T24","definition_or_measurement_approach":"Quantification of listed pro-inflammatory and pro-resolving lipid mediators in biological samples at T0 and T24."}
• {"endpoint_text":"- evaluation of cortical lesions (CLs) number and volume and their changes, evaluation of chronic active lesions number and evolution (such analysis will be performed by identifying rim-positive lesions on SWI), the rate of global and regional cortical thickness change using 3D T1 FFE sequences, longitudinal change of MTSat/MWF multiparametric combination will be computed in WM lesions and normal appearing white matter, longitudinal changes in the cross sectional area of the spinal cord.","definition_or_measurement_approach":"MRI-based measures including count and volume of cortical lesions, identification of rim-positive lesions on SWI, cortical thickness change using 3D T1 FFE, longitudinal MTSat/MWF multiparametric analyses in white matter lesions and NAWM, and spinal cord cross-sectional area changes."}
• {"endpoint_text":"- To evaluate the EDSS change before, during, and after the treatment","definition_or_measurement_approach":"EDSS scores assessed longitudinally (comparisons T0 vs T12 and T12 vs T24 as specified)."}
• {"endpoint_text":"- To evaluate changes in cognitive functioning from T0 to T24","definition_or_measurement_approach":"Neuropsychological assessments of cognitive functioning at baseline and 24 months to evaluate change."}
• {"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 per safety monitoring procedures."}

Italy

Earliest CTIS Part Ii Submission Date

13-06-2024

Latest Decision Or Authorization Date

06-08-2024

Processing Time Days

54

Number Of Sites

1

Number Of Participants

40

Primary sponsor

Full Name

Azienda Ospedaliera Universitaria Integrata Verona

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy