Evaluation of Siponimod on Chronic Intrathecal Inflammation in Secondary Progressive Multiple Sclerosis Patients
- Trial ID
- 2024-512283-65-00
- Protocol
- GR-2021-12373041
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **siponimod** in patients with secondary progressive multiple sclerosis (SPMS). This evaluation focuses on the drug's impact on advanced immunological measures of chronic inflammation, assessed in paired blood and cerebrospinal fluid (CSF) samples from a cohort of 40 SPMS patients. These patients are treated with siponimod and followed up for a minimum of two years. This objective is clinically relevant as it aims to understand the potential of siponimod in modulating chronic inflammation, which is a key factor in the progression of SPMS.
Secondary objectives include:
- Evaluating the effect of siponimod on MRI biomarkers of compartmentalized inflammation linked to disease progression.
- Assessing clinical, neuropsychological, and safety data in a real-life population of SPMS patients treated with siponimod.
Participants
The clinical trial involves **patients with secondary progressive multiple sclerosis (SPMS)**, focusing on the evaluation of siponimod's effect on advanced immunological measures of chronic inflammation. The study population includes both male and female participants aged between 18 and 65 years, with an active progressive MS course following an initial relapse clinical course. Participants are required to have an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.0 and must have entered the progressive phase of the disease less than five years prior to enrollment. The trial does not involve a vulnerable population. Female participants must not be pregnant or breastfeeding and are required to use highly effective contraception methods during the study. The sponsor has not provided information regarding the total number of participants. The selection criteria include the availability of specific MRI sequences and detailed clinical data on medical history, with neurological evaluations conducted at least twice in the past two years. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **siponimod** in patients with secondary progressive multiple sclerosis (SPMS). This is a randomized, double-blind, controlled trial with a primary objective to assess the drug's impact on advanced immunological measures of chronic inflammation in paired blood and cerebrospinal fluid (CSF) over a two-year period. The trial will involve a cohort of 40 SPMS patients, with the study duration estimated to conclude by April 2026. Participants will be administered **siponimod** in the form of film-coated tablets, with a maximum daily dose of 2 mg, and the treatment period will last up to 24 months.
The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (18-65 years), disease progression, and availability of specific MRI sequences. Following the screening, participants will undergo baseline assessments at T0, including high-dimensional flow cytometry and evaluation of CSF markers. Follow-up visits will occur periodically to monitor treatment emergent adverse effects (TEAEs) and serious adverse events (SAEs), as well as to assess changes in cognitive functioning, CSF oligoclonal bands, and other inflammatory markers. The end-of-study visit at T24 will involve comprehensive evaluations similar to those conducted at baseline.
Participant involvement is expected to last for the full 24-month treatment period unless conditions arise that necessitate early termination, such as significant adverse reactions or withdrawal of consent. The primary endpoint focuses on changes in CSF levels of CXCL13, a marker associated with B-cell accumulation and disease progression. Secondary endpoints include the characterization of immune cell subsets, evaluation of inflammation and neurodegeneration markers, and assessment of cortical lesions and spinal cord changes. The trial is categorized as a Phase IV study, indicating its focus on post-marketing surveillance to further understand the drug's effects in a real-world setting.
Treatment
The clinical trial involves the administration of **siponimod**, a chemical active substance, in the form of film-coated tablets. Two formulations of the medication are utilized: Mayzent 0.25 mg and Mayzent 2 mg, both produced by Novartis Europharm Limited. The active substance, siponimod, is also known by the synonym BAF312. The pharmaceutical form for both dosages is a film-coated tablet, designed for **oral use**. The maximum daily dose for the 0.25 mg formulation is 1250 micrograms, while the 2 mg formulation has a maximum daily dose of 2 milligrams. The treatment period for both formulations is capped at 24 months.
Participants in the trial will receive the experimental medication, siponimod, as part of the study protocol. The administration of the drug will be monitored to ensure compliance with the dosing schedule. The trial does not include any non-experimental treatments such as a placebo or comparator treatment. The primary objective of the trial is to evaluate the effect of siponimod on advanced immunological measures of chronic inflammation in patients with secondary progressive multiple sclerosis (SPMS). The study will involve a cohort of 40 SPMS patients, who will be treated with siponimod and followed up for a minimum of two years.
Efficacy
The efficacy of the investigational product, **siponimod**, in patients with secondary progressive multiple sclerosis (SPMS) will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the characterization of the drug's effect on cerebrospinal fluid (CSF) markers of chronic intrathecal inflammation, specifically measuring changes in the levels of CXCL13, a chemokine associated with B-cell accumulation and disease progression. This endpoint is based on existing literature and preliminary data that highlight the significance of CXCL13 in SPMS.
Secondary endpoints include a comprehensive evaluation of both intrathecal and paired blood adaptive and immune cell subsets using high-dimensional flow cytometry at baseline (T0) and after two years of treatment (T24). Additional assessments involve the evaluation of paired blood and CSF markers of inflammation and neurodegeneration, CSF oligoclonal bands status and number, and the main pro-inflammatory and pro-resolving lipids at T0 and T24. The study will also assess changes in cortical lesions (CLs) number and volume, chronic active lesions, global and regional cortical thickness, and longitudinal changes in multiparametric combinations in white matter lesions and normal appearing white matter. Furthermore, the Expanded Disability Status Scale (EDSS) change, cognitive functioning, and treatment emergent adverse effects (TEAE) and serious adverse events (SAE) will be evaluated at each follow-up visit.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 lesion on MRI acquired, in the previous 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
- 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)
- 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 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
- Patients homozygous for the CYP2C9 *3 *3 allele
- Immunodeficiency syndrome
- History of progressive multifocal leukoencephalopathy or cryptococcal meningitis
- Hematologic alterations (lymphocyte count or platelets not within normal limits)
- Rheumatic disease under specific treatment (including chronic use of steroid)
- Severe active infections (regard to positive result to HBV, HCV, HIV, Quantiferon)
- Active malignities
- 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
- Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN) or kidney dysfunction (serum creatinine not within normal limits dysfunction
- 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)
- 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
- Abnormal skin or ophthalmic examination
- Diabetes mellitus
- Pregnancy positive test or breastfeeding
- Fertile women who do not use highly effective methods of contraception
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 29 May 2023 | 40 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Mayzent 0.25 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 1250 | 24 | PRD7835928 |
Mayzent 2 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 2 | 24 | PRD7835936 |